Natural compounds from medicinal plants against COVID-19

Anton Kolodnitsky; Nikita Ionov; Irina Gravel; Vladimir Poroikov

doi:10.37349/eds.2023.00017

Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), known to cause the coronavirus disease 2019 (COVID-19), was declared a pandemic in early 2020. During the past time, several infections control methods have been developed. Nevertheless, all of them have certain limitations: uncertainty in duration, limited efficacy of vaccines, and lack of effective drugs for COVID-19 treatment. So, the issue of creating drugs for symptomatic and etiotropic therapy is still relevant. This review summarizes the current knowledge of using natural compounds as anti-SARS-CoV-2 agents by analysing the results of in vitro studies and completed clinical trials (CTs). Also, this work highlighted the most active molecules and discussed the possibility of using some compounds in clinical practice.

Keywords

SARS-CoV-2, COVID-19, medicinal plants, natural products, in vitro studies, clinical trials

Introduction

The coronavirus disease 2019 (COVID-19) pandemic is remaining an extremely serious public health problem in the world despite the declining numbers of infections and deaths. There were over 750 million confirmed cases of COVID-19. Currently, the pandemic has claimed approximately seven million lives as of February 2023 [1].

Problems with global access, uncertainty about the duration of protection and efficacy of existing vaccines, and the small number of World Health Organization (WHO)-approved drugs indicate the need for further research into new treatments for COVID-19 [2].

The growing interest to investigate the natural compounds against COVID-19 illustrated by the informational search in the PubMed database. Using query “(SARS-CoV-2 OR COVID-19) AND (natural compound OR phytocomponent OR phytoconstituent OR secondary metabolite)” one obtains 374 records in 2020, 804 records in 2021, and 794 records in 2022 (the data for 2022 is still incomplete on the time of manuscript preparation). It is their broad pharmacological spectrum and safety that make natural compounds a rich source of potential anti-coronavirus agents exhibiting symptomatic and etiotropic action [3–5].

This review has collected publications of in vitro studies that provide information on biochemical and cellular assays of natural compounds from medicinal plants. For clinical studies, we have analyzed the studies that evaluate the efficacy of single molecules of medicinal plants but have not considered extracts, since this makes it difficult to determine the effect of a particular molecule.

This study aims to provide information facilitating candidate selection studies for the initiation of clinical trials (CTs) and to evaluate the probability of using a natural compound as a treatment for COVID-19 based on the results of completed CTs. For this purpose, we reviewed several hundred relevant publications and selected the most active in vitro studies (Figure 1) that inhibit severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) targets [spike protein (S-protein), 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), and non-structural protein 13 (nsp13)] or reduce viral replication in various cell cultures [Vero E6, Calu-3, HEK293T-human angiotensin I converting enzyme 2 (ACE2), and Michigan Cancer Foundation-7 (MCF7)]; and report the results of CTs on the treatment of SARS-CoV-2 infection with phytocomponents from medicinal plants. The structure of the most active compounds in in vitro tests is shown below.

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Figure 1.

Examples of structures of phytocomponents from medicinal plants that demonstrated anti-coronavirus activity in biochemical or cellular assays

As one may see from Figure 1, ten phytocomponents are belonging to the class of flavonoids (baicalein, kaempferol, etc.), eleven to alkaloids (aloin, berbamine, etc.), while the others are quite diverse in chemical structure and could be broadly classified as “Compounds of other classes”.

The most active compounds in in vitro assays are discussed below. More in vitro data can be found in the Supplementary materials.

Inhibition of SARS-CoV-2 proteins in vitro

Blocking of S-protein/ACE2 interaction

Coronavirus S-protein plays a key role in the process of receptor recognition and cell membrane fusion. This protein consists of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain (RBD) that recognizes and binds to the ACE 2 host receptor. The S1 subunit, which induces the production of virus-neutralizing antibodies, is characterized by a high mutation rate, which may reduce the efficacy of vaccines and therapeutic antibodies. The S2 subunit ensures the fusion of the viral and cellular membranes. This process is activated by proteolysis, which releases the fusion peptide at the N-terminal portion of S2. The fusion peptide saturated with hydrophobic residues interacts with the cell membrane, triggering protein structural rearrangements, leading to membrane fusion and the entry of viral material into the cytoplasm. The two heptad repeat (HR) sites of the S2 subunit playing an important role in viral infections are highly conserved, both in structure and in the way they interact [6]. Inhibitors of RBD interaction with ACE2 may be used as anti-coronavirus agents.

We identified four phytocomponents of medicinal plants, which intimidate interaction between RBD and ACE-2 [7–9]. For Withanone potential activity was found in silico using docking and molecular dynamic simulation (scoring function value equals to −9.4 kcal/mol), which was confirmed in in vitro assay [half maximal inhibitory concentration (IC₅₀) = 0.33 ng/mL] [8]. For glycyrrhetinic acid, betulinic acid, and oleanolic acid, good estimates of binding to RBD were found in silico (scoring function values equal to –8.6, –8.1, and –8.2 kcal/mol, respectively). Evaluation of computational predictions in in vitro assays confirmed that those compounds inhibit the interaction of the RBD and ACE2 with IC₅₀ in the range from 0.1 μmol/L to 1 μmol/L [9].

Withanolides are naturally occurring chemical compounds. They are secondary metabolites produced via the oxidation of steroids and structurally consist of a steroid backbone bound to a lactone or its derivatives. They have medicinal value including anti-inflammation, anti-cancer, adaptogenic, and anti-oxidant effects. Withanone is a phytocomponent of Withania somnifera (Linn.) Dunal., also known as Ashwagandha in Indian Ayurvedic medicine [10].

3CLpro inhibitors studies in vitro

The main protease 3CLpro of SARS-CoV-2 plays a crucial role in the viral life cycle. Among all potential viral target proteins, the main protease stands out as the most highly conserved enzyme. It is also worth noting that human proteases with similar cleavage specificity do not exist; therefore, 3CLpro inhibitors are highly likely to be nontoxic [11, 12].

Sixty-six natural compounds from medicinal plants were examined for their ability to inhibit the 3CLpro [13–21]. Compounds with the highest IC₅₀ values are presented in Table 1.

Table 1.

List of the most potent phytocomponents inhibiting 3CLpro

Phytocomponent	IC₅₀ (μmol/L)	References	Scoring function (kcal/mol)	References
Epicatechin gallate	1.58	[13]	–8.2	[22]
CCG 50014*	0.23; 0.15	[13]	NA	NA
Baicalein	0.02; 0.94	[13]	–7.3	[23]
Dihydromyricetin	0.18	[13]	–6.2	[24]
Hematoxylin	0.22	[13]	NA	[25]
Schaftoside	1.73	[15]	–8.4	[26]
Sennoside A	1.59	[13]	–8.6	[27]

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*: also known as 4-(4-fluorobenzyl)-2-p-tolyl-1,2,4-thiadiazolidine-3,5-dione. NA: not available

As one may see from Table 1, dihydromyricetin, baicalein, hematoxylin, and CCG 50014 are the most active 3CLpro inhibitors with submicromolar IC₅₀ values.

Myricetin is a natural flavonol compound that can be found in many plants. According to the literature, myricetin and its derivatives showed anti-inflammatory, antioxidant, antibacterial, and antiviral activities [28].

Hematoxylin is a naturally occurring compound derived from the logwood tree, Haematoxylon campechianum. As staples of histopathological studies, hematoxylin has become the inimitable scaffold on which many of our dermatological diagnoses are made [29, 30].

The major constituent and most important polyphenolic catechin in green tea (Thea sinensis L.) is epigallocatechin-3-gallate, which has shown numerous beneficial properties, such as anti-inflammatory ability, antioxidative properties, and antiviral effects against various viruses [31].

PLpro inhibitors studies in vitro

PLpro of SARS-CoV-2 plays an important role in virus maturation, disruption of host inflammation regulation, and antiviral immune response PLpro’s multiple functions make it a promising anti-coronavirus drug target [32].

Thirty-four phytocomponents were analyzed for inhibition of papain-like cysteine protease [14, 15, 21, 33–36]. Compounds with the best results in the context of inhibition activity are shown in Table 2.

Table 2.

List of the most potent phytocomponents inhibiting PLpro

Name of chemical compound	IC₅₀ (μmol/L)	References
Methyl 3,4-dihydroxybenzoate	3.76	[33]
p-Hydroxybenzaldehyde	3.99	[34]
Schaftoside	3.91	[15]

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Herba Desmodii styracifolii is widely used in Traditional Chinese Medicine (TCM) for inflammation, pyrexia, and kidney stone treatment. Schaftoside, one of the most abundant flavonoids of this plant, possessed different physiological activities including anti-inflammatory. We also found in literature in silico data which show that the scoring function of schaftoside interaction with PLpro is about –8.7 kcal/mol [37, 38].

RdRp in vitro study

The RdRp domain (about 600 amino acid residues) is a replicase, which in complex with other proteins (nsp7, nsp8) realizes replication of genomic RNA and translation of subgenomic RNA. Significant similarity at the level of amino acid sequences is found in different families of viruses with a single-stranded genome sequence. Thus, there is a variety of opportunities for drug repositioning [39, 40].

Information was collected on two compounds (baicalin, baicalein). Both confirmed the capability of chain-termination during RNA synthesis in an in vitro study that may cause by different mechanisms such as inhibition of replicase. In silico tests showed that both compounds could strongly bind to SARS-CoV-2 RdRp with an estimated binding energy (scoring function) of about −8.7 kcal/mol and −7.8 kcal/mol, respectively [41].

Baicalein and his glucuronide baicalin are flavones and the main active compounds of Scutellaria baicalensis George, that are widely used in TCM for treating infection of multiple different viruses. These compounds also exhibit inhibitory activity against the main protease 3CLpro [42].

nsp13 in vitro study

The nsp13 protein functions as a helicase using ATP, by uncoupling double-stranded RNA intermediates. This protein is also involved in cap formation. nsp13 helicase is the key component of the replication-transcription complex (RTC), which is necessary to complete its infectious life cycle [43].

Twenty-two compounds were examined [44, 45]. Compounds with the most inhibition activity are presented in the Table 3 and are taken from paper by Corona et al. [44]. The results of in silico estimations were extracted from different sources.

Table 3.

List of compounds with the highest IC₅₀ value [44]

Name of chemical compound	IC₅₀ (μmol/L)	Scoring function (kcal/mol)	References to in silico
Baicalein	2.9	–8.9	[46]
Kaempferol	0.76	–6.9	[47]
Licoflavone C	1.34	NA	NA
Myricetin	0.41	–7.0	[47]
Quercetin	0.53	–6.9	[47]

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Kaempferol is a flavonoid extracted from some medicinal herb like Kaempferia galanga L. Pharmacological effects of kaempferol including antioxidant, anti-inflammatory, antimicrobial, and antiviral properties were also reported [48–50].

Licoflavone C is one of the main flavonoids of licorice (Glycyrrhizae Radix or Liquiritiae Radix) that is traditionally used to treat various diseases including inflammation and gastric ulcers. The protective effect of licorice flavonoids may at least in part be due to their antioxidant activity through the nuclear factor erythroid 2-related factor 2 pathway and anti-inflammatory activity through the nuclear factor kappa-light-chain-enhancer of activated B cells pathway [51].

HEK293T-ACE2 in vitro study

HEK293T-ACE2 is constructed by transduction of ACE2 into HEK293T cells, followed by stable cell selection. These cell lines express ACE2 messenger RNA (mRNA) at high levels on the cell surface and are amenable to infection by viruses [52].

One hundred and seventy-five compounds were tested on this cell line [20, 45, 53–57]. The most active compounds in the context of preventing the infiltration of the virus into the cell are shown in Table 4. All information in the table was extracted from the He et al. [20] study.

Table 4.

List of compounds with the highest results in cell line HEK293T-ACE2 [20]

Name of chemical compound	EC₅₀ (μmol/L)	CC₅₀ (μmol/L)	SI
Aloperine	0.28	> 50	> 176.87
Berbamine	1.28	> 50	> 38.94
Cepharanthine	0.32	> 50	> 158.58
Dauricine	1.43	> 50	> 34.99
Fangchinoline	0.94	> 50	> 53.39
Hernandezine	0.11	> 50	> 448.83
Isofangchinoline	1.11	> 50	> 45
Isoliensinine	0.923	> 50	> 54.17
Liensinine	1	> 50	> 49.8
Neferine	0.95	> 50	> 52.87
Tetrandrine	0.9	> 50	> 55.8

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EC₅₀: half maximal effective concentration; CC₅₀: half cytotoxic concentration; SI: selectivity index

Aloperine, a quinolizidine-type alkaloid, was first isolated from the seeds and leaves of the herbal plant, Sophora alopecuroides L. It has known for its antitumor, anti-microbial, anti-oxidative, and immune regulator effects [58].

Cepharanthine is the only approved drug for human use in the large class of bisbenzylisoquinoline alkaloid. This natural product, mainly isolated from the plant Stephania cephalantha Hayata and exhibits multiple pharmacological properties including anti-oxidative, anti-inflammatory, immuno-regulatory, and anti-viral [59].

Hernandezine is an alkaloid isolated from the Chinese medicinal herb manyleaf meadowure rhizome and root. Hernandezine is tested like an anticancer and antidiabetic agent. Also, in vitro assay demonstrates its capability to inhibit tumor necrosis factor alpha (TNF-α) expression, which causes an anti-inflammatory effect [60–62].

Berbamine is one of the main components in various species of Berberis L. This substance is known for its anti-cancer properties that are realized by various mechanisms, including anti-inflammatory [63–65].

Vero E6 in vitro study

Vero E6 is a cell line exhibiting epithelial morphology that was isolated from the kidney of an African green monkey. The Vero cells are the most employed for their high susceptibility to the replication of a wide range of viruses, including SARS-CoV- 2 [66].

Twenty-five compounds were tested on this cell line [7, 14, 15, 17, 43, 56, 67–72]. The list of compounds that most effectively inhibit SARS-CoV-2 replication is shown in Table 5.

Table 5.

List of compounds with the best EC₅₀ values obtained in cell line Vero E6

Name of chemical compound	EC₅₀ (μmol/L)	References
Punicalagin	0.196	[45]
Retusin	0.4	[67]
Salvianolic acid C	3.41	[56]
Aloin	0.095	[72]
Cepharanthine	0.35	[71]

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Punicalagin is an ellagitannin found in the peel of the pomegranate (Punica granatum L.) and is its main constituent. A number of studies prove the anti-inflammatory and antioxidant properties of this compound [73].

Aloin is an active ingredient found in the leaves of medicinal plants of the genus Aloe. Aloin has been investigated in in vitro and in vivo research for its anti-inflammatory, anticancer, antibacterial, and antioxidant activities [74].

Calu-3 in vitro study

Calu-3 cells are a human lung epithelial cell line that can support the propagation of SARS-CoV-2. These cells can promote the replication of SARS-CoV-2 viruses expressing the spike gene with an intact furin cleavage site [75].

Fifteen compounds were tested on this cell line [41, 53, 67, 76, 77]. The list of compounds that most effectively inhibit SARS-CoV-2 replication is shown in Table 6.

Table 6.

List of compounds with the best EC₅₀ values obtained in cell line Calu-3

Name of chemical compound	EC₅₀ (μmol/L)	CC₅₀ (μmol/L)	SI	References
Baicalein	1.2	91	76	[41]
Fisetin	2.03	256	126	[76]
Homofascaplysin A	1.1	5	5	[77]
Kumatakenin	0.3	214	716	[67]
Myricetin	0.91	716	787	[76]
Quercetin	2.4	852	355	[76]
Retusin	0.4	3,333	8,333	[67]

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Fisetin is a flavonol that is an isolate from Rhus cotinus L. A number of in vitro studies have confirmed the antioxidant and anti-inflammatory biological activity [78, 79].

Retusin is a methylated flavonoid that occurs in different plants like Larrea cuneifolia, Solanum pubescens, and Siparuna cristata. In vitro studies showed the potential free radical-scavenging capacities of this compound [80].

MCF7 in vitro study

MCF7 are epithelial cells isolated from the breast tissue of a 69-year-old female patient with metastatic adenocarcinoma. These cells demonstrate a high replication capacity of SARS-CoV-2 [81, 82].

Three compounds (caffeic acid phenethyl ester, Withaferin-A, and Withanone) were tested on this cell line. All of them were characterized as active inhibitors of SARS-CoV-2 replication [83].

Caffeic acid phenethyl ester is a natural bioactive compound, which occurs in many plants, and also has known as the most extensively investigated active component of ethanol and butanol extracts of the plant which possess many biological activities including antibacterial, antiviral, antioxidant, and anti-inflammatory effects [84–86].

Clinic trials

As a result of the analysis of available data on CTs, 265 trials of potential drugs for the etiotropic and symptomatic treatment of COVID-19 are underway or have been completed. Of these, 32 were conducted using medicinal plant compounds as a pharmaceutical substance. Summarizes information about these studies is presented in Table 7 [87–143]. The results of CTs were extracted from corresponding publications.

Table 7.

List of results of CTs of potential drugs for the treatment of COVID-19 using natural compounds from medicinal plants

Name of chemical compound	Study design; sample size (control group/investigate group)	References on protocol studies	Results	References on results
Artemisinin	An open-label, non-randomized, controlled trial; 41 (23/18)	[87]	Positive effects	[111]
Artesunate	Not fully described; 43 (25/18)	-	Positive effects	[112]
Berberine	Not fully described; 35 (17/18)	-	No significant difference	[113]
Cannabidiol	A single-center, randomized, parallel, double-blind, placebo-controlled CT; 104 (52/52)	[88]	No significant difference	[114]
Colchicine	A randomized controlled CT; 90 (45/45)	[89]	Positive effects	[115]
Colchicine	A randomized, open-labeled, CT; 80 (40/40)	[90]	Positive effects	[116]
Colchicine	A randomized, double-blinded, placebo-controlled CT; 72 (36/36)	[91]	Positive effects	[117]
Colchicine	A multicenter, randomized CT; 152 (89/63)	[92]	Positive effects	[118]
Colchicine	A randomized controlled CT; 112 (34/78)	-	Positive effects	[119]
Colchicine	A randomized controlled CT; 336 (165/171)	-	Positive effects	[120]
Curcumin	A randomized double-blind placebo-controlled trial; 48 (24/24)	[93]	Positive effects	[121]
Curcumin	A randomized controlled, double-blind, placebo-controlled CT; 60 (30/30)	[94]	Positive effects	[122]
Curcumin	A non-randomized open-label, parallel-group CT; 41 (21/20)	[95]	Positive effects	[123]
Curcumin	Randomized double-blind CT; 40 (20/20)	[96]	Positive effects	[124]
Curcumin	A non-randomized open-label, parallel-group CT; 60 (30/30)	[97]	Positive effects	[125]
Curcumin	A randomized, double-blind, placebo-controlled trial; 50 (25/25)	[98]	Positive effects	[126]
Curcumin	A randomized, parallel-group trial; 140 (70/70)	[99]	Positive effects	[127]
Glycyrrhizin	A single-center, randomized, double-blind, placebo-controlled CT; 50 (25/25)	[100]	Positive effects	[128]
Glycyrrhizin	A randomized triple-blind placebo-controlled CT; 125 (62/63)	[101]	Positive effects	[129]
Glycyrrhizin	Retrospective study [in study compares two groups of people: those with the disease under study (cases) and a similar group of people who do not have the disease (controls)]; 147 (66/81)	-	Positive effects	[130]
Hesperidin	Control group, with parallel, double-blind, and randomized groups; 40 (20/20)	[102]	No significant difference	[131]
Hesperidin	Randomized, double-blind, placebo-controlled study; 216 (109/107)	[103]	Positive effects	[132]
Luteolin	Randomized-controlled pilot study; 12 (7/5)	-	Positive effects	[133]
Luteolin	Randomized-controlled study; 69 (59/10)	-	Positive effects	[134]
Plitidepsin	Randomized, parallel, open-label; 30 (15/15)	[104]	Positive effects	[135]
Plitidepsin	Case study (research of one case); 1	-	Positive effects	[136]
Quercetin	Single center, randomized, controlled trial; 429 (380/49)	[105]	No significant differences	[137]
Quercetin	Randomized, parallel assignment, placebo-controlled CT; 60 (30/30)	[106]	Positive effects	[138]
Quercetin	Single-center, prospective, randomized, controlled cohort study; 120 (60/60)	[107]	Positive effects	[139]
Quercetin	Pilot, randomized, controlled and open-label CT; 42 (21/21)	-	Positive effects	[140]
Resveratrol	Randomized, placebo-controlled trial; 30 (14/16)	[108]	No significant differences	[141]
Resveratrol	Not fully described; 230 (200/30)	[109]	Positive effects	[142]
Resveratrol	Double-blind, randomized, placebo-controlled trial; 100 (50/50)	[110]	Positive effects	[143]

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-: not applicable

As shown in Table 7, a total of 33 CTs were. Of these, 28 reported a positive effect and 5 reported no significant difference. These studies considered 12 compounds and only 2 of them not reported positive results (berberine and cannabidiol) [87–143]. The most studied compounds are considered below.

Curcumin

Curcumin is a polyphenol contained in the root of the Curcuma longa. This compound has a wide range of pharmacological effects, including anti-inflammatory properties. One possible mechanism is inhibition of nuclear factor kappa-light-chain-enhancer of activated B, which leads to lower levels of cytokines and proinflammatory chemokines such as interleukin-1β (IL-1β), IL-18, IL-6, TNF-α, and monocyte chemoattractant protein-1 [144]. The result of some in silico and in vitro studies present in Figure 2.

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Figure 2.

In silico and in vitro results of curcumin

The wide range of pharmacological properties is not the only reason why this molecule was chosen as a subject in CTs. As can be seen in Figure 2, curcumin also demonstrates inhibitory activity to SARS-CoV-2 in in silico and in vitro studies [145–147]. This suggests that the effect of curcumin not be limited to its anti-inflammatory properties, but may also be the result of direct anti-SARS-CoV-2 action.

In this review, 7 CTs were selected in which curcumin was studied as a potential drug for the treatment of COVID-19. A summary of these studies is presented in Table 8.

Table 8.

Results of CTs of curcumin

CT phase	Evaluated parameters	Patient groups (placebo/control)	Results	References
Not specified	Clinical symptoms, O₂ saturation, general analysis blood, C-reactive protein (CRP), CT	24/24	Decrease in overall Wisconsin Questionnaire score. Level differentiation, high-sensitivity CRP levels, and the degree of lung damage on CT were not different between the two groups.	[93]
3	Levels of serum secretion of inflammatory cytokines IL-1β, IL-6, and TNF-α	30/30	Curcumin can significantly increase the frequency and function natural killer cells compared to the group that received a placebo.	[94]
3	Symptoms (fever, chills, myalgia, cough), O₂ saturation	21/20	Reduced hospitalization time, O₂ saturation was significantly higher in the group treatment.	[95]
Not specified	Clinical signs and gene expression of T-box transcription factor 21, GATA binding protein 3, RAR-related orphan receptor C, and forkhead box P3, serum levels of cytokines interferons-γ (IFN-γ), IL-4, IL-17, and transforming growth factor beta	20/20	Serum levels of IFN-γ and IL-17 decreased, and IL-4 and transforming growth factor beta increased in the curcumin group compared with the placebo. TBX21 and FOXP3 gene expression was significantly reduced.	[96]
3	Clinical signs and mRNA of IFN-γ, IL-1β, IL-6, monocyte chemoattractant protein-1, and TNF-α and levels of the inflammatory mediators IL-1β, IL-6, and TNF-α in serum	30/30	Clinical manifestations and laboratory parameters improved after curcumin treatment, IFN-γ and TNF-α mRNA expression decreased significantly. There was a significant difference between curcumin and the control group in the expression of IFN-γ, IL-1β, and IL-6; and a significant difference between curcumin and controls in serum levels of IL-1β.	[97]
Not studied	Clinical symptoms, O₂ saturation	70/70	Patients with moderate and severe symptoms who received curcumin treatment showed an earlier recovery compared to patients in the control group. Curcumin treatment shortened the duration of hospitalization in patients with moderate to severe symptoms; the curcumin treatment group had fewer deaths.	[99]

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As can be seen from Table 8, all presented CTs indicate an improvement in clinical and biochemical parameters in the curcumin treatment groups compared with the placebo. However, the design features of these CTs, which include small patient sample groups and lack of “blinding” do not allow objective conclusions to be drawn about the feasibility of curcumin used in the general population.

Quercetin

Quercetin is a natural flavonoid found in various fruits, vegetables, leaves, and grains like red onion or bog blueberry. It is well known for its antioxidant and anti-inflammatory properties. Quercetin prevents TNF-α from directly activating extracellular signal-related kinase, which are potent inducers of inflammatory gene expression and protein secretion [148].

As in the case of curcumin, interest in quercetin is supported not only by its safety and anti-inflammatory activity but also by the positive results of the in silico and in vitro studies discussed earlier and summarized in Figure 3. And, as before, we can assume that the anti-COVID-19 properties are may achieved both by the symptomatic and etiotropic type of action.

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Figure 3.

In silico and in vitro results of quercetin

Two CTs were reviewed for quercetin (Table 9).

Table 9.

Quercetin CT results

CT phase	Estimated options	Patient groups (placebo/control)	Results	References
3	Level CRP, alkaline phosphatase, lactate dehydrogenase (LDH)	30/30	Quercetin administration was significantly associated with earlier discharge and decreased serum alkaline phosphatase levels, CRP, and LDH.	[138]
Unknown	Clinical symptoms, polymerase chain reaction test	Standard therapy + quercetin—21; standard therapy—21	In the standard therapy group, 2 patients received a negative test for SARS-CoV-2 and 4 patient’s symptoms partially improved. After 2 weeks, the remaining 5 patients in the quercetin group tested negative for SARS-CoV-2, then while in the standard care group, of the remaining 19 patients, 17 showed a negative result at week 2, one negative result at week 3, and one patient, still positive, died at day 20. On the background of quercetin therapy, LDH, and ferritin levels decreased, CRP and D-dimer.	[140]

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Quercetin CTs data presented in Table 9 show a positive effect of the drug on the course of COVID-19 in combination with remdesivir or favipiravir in small samples of patients. However, additional trials are required to confirm the efficacy.

Colchicine

Colchicine is a plant alkaloid isolated from plants of the genus Colchicum L. It is a drug approved by the Food and Drug Administration as a treatment for gout, that has a wide range of anti-inflammatory effects, including decreasing the expression of adhesion molecules on neutrophil membranes and modulating the production of anti-inflammatory cytokines (IL-1 and IL-6) as well as TNF-α. These properties and a long history of use have attracted the attention of researchers to this molecule as a potential anti-COVID-19 agent [149]. Six CTs were selected, the results of which are shown in Table 10.

Table 10.

Colchicine CT results

Phase	Estimate options		Patient groups (placebo/control)	Results	References
4	Need for artificial ventilation, length of stay in intensive care, and mortality		Ivermectin + colchicine + standard care—45; colchicine + standard care—45; standard care—45	Colchicine was associated with clinically significant reductions in oxygen demand days, intensive care unit length of stay, and less mortality, while ivermectin added no beneficial effect.	[115]
2	Need for artificial lung ventilation, length of stay intensive therapy, mortality		40/40	Serum ferritin levels in most patients who received colchicine, returned to normal in contrast to the control group, whose serum ferritin levels remained high. Similarly, the mean CRP and D-dimer values after treatment among participants in the colchicine group were significantly lower than in the control group. Patients in the colchicine group stayed in the hospital for a shorter period compared with the control group.	[116]
3	Need for artificial lung ventilation, length of stay in intensive care, mortality		36/36	Colchicine reduced the duration of additional oxygen therapy and hospitalization. The drug was well tolerated. Since death was a rare event, one cannot argue that colchicine reduced COVID-19 mortality.	[117]
3	CT	Colchicine + standard therapy—89; standard therapy—63		According to this study, colchicine can improve clinical outcomes and reduce pulmonary infiltration in patients with COVID-19.	[118]
Not studied about	Inflammatory markers, mortality	Colchicine + standard treatment—34; standard treatment—78		Patients in the colchicine group had lower mortality rates, lower intubation rates, and a higher percentage of discharge.	[119]
Not studied about	Length of hospital stay	Colchicine + standard treatment—165; standard treatment—171		The average length of hospital stay in the colchicine group was significantly short.	[120]

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As can be seen in Table 10, in the studied trials colchicine was used in combination with COVID-19 standard therapy that is not specified in the available publications. In 6 of them, the effectiveness of colchicine in combination with standard therapy was established. Reduced hospitalization time, good tolerability of the drug, and improved biochemical parameters were shown. However, these studies are characterized by disadvantages similar to those of curcumin. It is also worth noting that in the latest WHO recommendations, colchicine is not recommended for use in patients with non-severe COVID-19.

Possible synergistic/additive effects of secondary metabolites

Since the present review considers mainly natural compounds from medicinal plants, we evaluated the prospects for studying the anti-coronaviral activity of plant extracts taking into account the potential synergistic/additive action of their phytocomponents. We found groups of compounds represented in the phytochemical composition of a single plant during the analysis of our results. Information about the content of the previously discussed compounds in plants is given in Table 11.

Table 11.

The list of plants in the phytochemical composition of which the largest number of phytochemical components considered

Plant’s name	Compound’s name	References
Polygonum aviculare L. (Polygonaceae)	Kaempferol; myricetin; oleanolic acid; luteolin; quercetin	[150]
Vitis vinifera L. (Vitaceae)	Myricetin; kaempferol; oleanolic acid; resveratrol; quercetin; luteolin	[151]
Nelumbo nucifera Gaertn. (Nelumbonaceae)	Isoliensinine; liensinine; neferine	[152]
Punica granatum L. (Punicaceae)	Luteolin; betulinic acid; punicalagin	[153]

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As shown by Yu et al. [150], kaempferol, myricetin, luteolin, and quercetin can be isolated from ethanol and butanol extracts of the plant Polygonum aviculare L. Kaempferol, quercetin, and myricetin are capable of inhibiting nsp13 (Table 3) as described above. Additionally, myricetin has been described as having an inhibitory activity against 3CLpro (Table 1) and quercetin has been demonstrated to inhibit viral replication on Calu-3 cells (Table 6). Two CTs of luteolin and 2 CTs of quercetin have shown a positive effect on the course of COVID-19 (Table 7). The described results make it reasonable to test ethyl and butanol extracts of Polygonum aviculare L. for their antiviral activity taking into account the possible synergistic/additive effects of its constituent chemical compounds.

Vitis vinifera L. has a similar composition of phytocomponents with laboratory-confirmed anti-coronaviral activity. It contains resveratrol for which the inhibition of coronavirus replication on Vero E6 cells was confirmed, as well as a positive effect on the course of COVID-19 in two CTs (Table 7) [154] in addition to the phytocomponents described above. Laboratory testing of the extract from the leaves of Vitis vinifera L. was carried out by Zannella et al. [151]. This study established the possibility of inhibiting SARS-CoV-2 replication in Vero cells.

Isoliensinine, liensinine, and neferine are phytocomponents of Nelumbo nucifera Gaertn. that can be isolated from its seeds. These compounds have been shown to inhibit SARS-CoV-2 entry into HEK293T-ACE2 cells. These facts discuss the feasibility of testing the anticoronavirus activity of Nelumbo nucifera Gaertn. seed extract.

The inhibition of viral entry into the cell and the inhibition of viral replication were shown in biochemical and cellular assays, or betulinic acid and punicalagin, respectively. However, as shown in a study by de Oliveira et al. [155], an extract from the rind of Punica granatum L. demonstrated not only the ability to inhibit virus entry into the cell by interaction with the S-protein but also a decrease in 3CLpro activity.

Conclusions

In this review, we summarized the current information about compounds from medicine plants that inhibit SARS-CoV-2 targets, reduce its replication in cell lines and/or studied different CTs. In in vitro assay, most research compounds are flavonoids like baicalein, kaempferol, myricetin, quercetin, and others. They demonstrate good inhibition activity in biochemical and cell assay. Since flavonoids have long been used as dietary supplements and their anti-inflammatory and immunostimulatory activity have been supported by a number of studies, they may be good candidates to launch new CTs or to start larger and more reliable studies for previously clinically tested compounds.

In spite of the fact that in the majority of CTs, preparations containing compounds of natural origin obtained positive results, it is extremely difficult to draw reliable conclusions about the effectiveness and prospects of the studied compounds. This is primarily due to the design of the studies themselves and the small groups of subjects. More than 90% of the studies were performed without blind control. Among the trials presented, there are trials with contradictory results under the same conditions. However, given the fact that for most of the presented chemical compounds a wide experience of use as dietary supplements and a low probability of side effects is available, some of these phytocomponents might be an effective adjunct to the standard therapy according to the WHO recommendations.

Abbreviations

3CLpro:	3-chymotrypsin-like protease
ACE2:	angiotensin I converting enzyme 2
COVID-19:	coronavirus disease 2019
CTs:	clinical trials
IC₅₀:	half maximal inhibitory concentration
IL-1β:	interleukin-1β
MCF7:	Michigan Cancer Foundation-7
mRNA:	messenger RNA
nsp13:	non-structural protein 13
PLpro:	papain-like protease
RBD:	receptor-binding domain
RdRp:	RNA-dependent RNA polymerase
SARS-CoV-2:	severe acute respiratory syndrome coronavirus-2
S-protein:	spike protein
TNF-α:	tumor necrosis factor alpha
WHO:	World Health Organization

Supplementary materials

The supplementary material for this article is available at: https://www.explorationpub.com/uploads/Article/file/100817_sup_1.pdf.

Declarations

Author contributions

AK: Data curation, Visualization, Writing—original draft. NI: Data curation, Writing—original draft. IG and VP: Conceptualization, Supervision.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

The study is performed in the framework of the Program for Basic Research in the Russian Federation for a long-term period (2021–2030) project No. [121102900156-6]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

WHO coronavirus (COVID-19) dashboard [Internet]. World Health Organization; [cited 2023 Feb 9]. Available from: https://covid19.who.int/

François Lamontagne, Arnav Agarwal, Bram Rochwerg, Reed AC Siemieniuk, Thomas Agoritsas, Lisa Askie, et al. A living WHO guideline on drugs for covid-19. BMJ. 2020;370:m3379. Erratum in: BMJ. 2022;377:o1045. [DOI] [PubMed]

Rishton GM. Natural products as a robust source of new drugs and drug leads: past successes and present day issues. Am J Cardiol. 2008;101:S43–9. [DOI] [PubMed]

Musarra-Pizzo M, Pennisi R, Ben-Amor I, Mandalari G, Sciortino MT. Antiviral activity exerted by natural products against human viruses. Viruses. 2021;13:828. [DOI] [PubMed] [PMC]

Omrani M, Keshavarz M, Nejad Ebrahimi S, Mehrabi M, McGaw LJ, Ali Abdalla M, et al. Potential natural products against respiratory viruses: a perspective to develop anti-COVID-19 medicines. Front Pharmacol. 2021;11:586993. [DOI] [PubMed] [PMC]

Rabaan AA, Al-Ahmed SH, Haque S, Sah R, Tiwari R, Malik YS, et al. SARS-CoV-2, SARS-CoV, and MERS-COV: a comparative overview. Infez Med. 2020;28:174–84. [PubMed]

Balkrishna A, Pokhrel S, Singh H, Joshi M, Mulay VP, Haldar S, et al. Withanone from Withania somnifera attenuates SARS-CoV-2 RBD and host ACE2 interactions to rescue spike protein induced pathologies in humanized zebrafish model. Drug Des Devel Ther. 2021;15:1111–33. [DOI] [PubMed] [PMC]

Carino A, Moraca F, Fiorillo B, Marchianò S, Sepe V, Biagioli M, et al. Hijacking SARS-CoV-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on the receptor binding domain. Front Chem. 2020;8:572885. [DOI] [PubMed] [PMC]

Kim YS, Kwon EB, Kim B, Chung HS, Choi G, Kim YH, et al. Mulberry component kuwanon C exerts potent therapeutic efficacy in vitro against COVID-19 by blocking the SARS-CoV-2 spike S1 RBD:ACE2 receptor interaction. Int J Mol Sci. 2022;23:12516. [DOI] [PubMed] [PMC]

10.

Vaishnavi K, Saxena N, Shah N, Singh R, Manjunath K, Uthayakumar M, et al. Differential activities of the two closely related withanolides, Withaferin A and Withanone: bioinformatics and experimental evidences. PLoS One. 2012;7:e44419. [DOI] [PubMed] [PMC]

11.

Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, et al. Structure of M^pro from SARS-CoV-2 and discovery of its inhibitors. Nature. 2020;582:289–93. [DOI] [PubMed]

12.

Tahir Ul Qamar M, Alqahtani SM, Alamri MA, Chen LL. Structural basis of SARS-CoV-2 3CL^pro and anti-COVID-19 drug discovery from medicinal plants. J Pharm Anal. 2020;10:313–9. [DOI] [PubMed] [PMC]

13.

Kuzikov M, Costanzi E, Reinshagen J, Esposito F, Vangeel L, Wolf M, et al. Identification of inhibitors of SARS-CoV-2 3CL-Pro enzymatic activity using a small molecule in vitro repurposing screen. ACS Pharmacol Transl Sci. 2021;4:1096–110. [DOI] [PubMed] [PMC]

14.

Chen Z, Cui Q, Cooper L, Zhang P, Lee H, Chen Z, et al. Ginkgolic acid and anacardic acid are specific covalent inhibitors of SARS-CoV-2 cysteine proteases. Cell Biosci. 2021;11:45. [DOI] [PubMed] [PMC]

15.

Yi Y, Zhang M, Xue H, Yu R, Bao YO, Kuang Y, et al. Schaftoside inhibits 3CL^pro and PL^pro of SARS-CoV-2 virus and regulates immune response and inflammation of host cells for the treatment of COVID-19. Acta Pharm Sin B. 2022;12:4154–64. [DOI] [PubMed] [PMC]

16.

Chiou WC, Chen JC, Chen YT, Yang JM, Hwang LH, Lyu YS, et al. The inhibitory effects of PGG and EGCG against the SARS-CoV-2 3C-like protease. Biochem Biophys Res Commun. 2022;591:130–6. [DOI] [PubMed] [PMC]

17.

Park JY, Kim JH, Kwon JM, Kwon HJ, Jeong HJ, Kim YM, et al. Dieckol, a SARS-CoV 3CL^pro inhibitor, isolated from the edible brown algae Ecklonia cava. Bioorg Med Chem. 2013;21:3730–7. [DOI] [PubMed] [PMC]

18.

Nguyen TTH, Jung JH, Kim MK, Lim S, Choi JM, Chung B, et al. The inhibitory effects of plant derivate polyphenols on the main protease of SARS coronavirus 2 and their structure–activity relationship. Molecules. 2021;26:1924. [DOI] [PubMed] [PMC]

19.

Shahhamzehei N, Abdelfatah S, Efferth T. In silico and in vitro identification of pan-coronaviral main protease inhibitors from a large natural product library. Pharmaceuticals. 2022;15:308. [DOI] [PubMed] [PMC]

20.

He CL, Huang LY, Wang K, Gu CJ, Hu J, Zhang GJ, et al. Identification of bis-benzylisoquinoline alkaloids as SARS-CoV-2 entry inhibitors from a library of natural products. Signal Transduct Target Ther. 2021;6:131. [DOI] [PubMed] [PMC]

21.

Li Z, Xie H, Tang C, Feng L, Ke C, Xu Y, et al. Flavonoids from the roots and rhizomes of Sophora tonkinensis and their in vitro anti-SARS-CoV-2 activity. Chin J Nat Med. 2022;21:65–80. [DOI] [PubMed] [PMC]

22.

Ghosh R, Chakraborty A, Biswas A, Chowdhuri S. Evaluation of green tea polyphenols as novel corona virus (SARS CoV-2) main protease (Mpro) inhibitors – an in silico docking and molecular dynamics simulation study. J Biomol Struct Dyn. 2021;39:4362–74. [DOI] [PubMed] [PMC]

23.

Azam F, Eid EEM, Almutairi A. Targeting SARS-CoV-2 main protease by teicoplanin: a mechanistic insight by docking, MM/GBSA and molecular dynamics simulation. J Mol Struct. 2021;1246:131124. [DOI] [PubMed] [PMC]

24.

Satyanarayana S, Dileep K, Shiva P, Kameshpandian P, Gayathri P, Swathi B. A computational approach on the activity of hesperidin as antagonist for proteins of SARS-CoV-2. BioNanoScience. 2021;10:2571–7. [DOI]

25.

Chen J, Zhou X, Fu L, Xu H. Natural product-based screening for lead compounds targeting SARS CoV-2 M^pro. Pharmaceuticals (Basel). 2023;16:767. [DOI] [PubMed] [PMC]

26.

Maddah M, Bahramsoltani R, Yekta NH, Rahimi R, Aliabadi R, Pourfath M. Proposing high-affinity inhibitors from Glycyrrhiza glabra L. against SARS-CoV-2 infection: virtual screening and computational analysis. New J Chem. 2021;45:15977–95. [DOI]

27.

Khamto N, Utama K, Tateing S, Sangthong P, Rithchumpon P, Cheechana N, et al. Discovery of natural bisbenzylisoquinoline analogs from the library of Thai traditional plants as SARS-CoV-2 3CL^Pro inhibitors: in silico molecular docking, molecular dynamics, and in vitro enzymatic activity. J Chem Inf Model. 2023;63:2104–21. [DOI] [PubMed]

28.

Liu T, Peng F, Cao X, Liu F, Wang Q, Liu L, et al. Design, synthesis, antibacterial activity, antiviral activity, and mechanism of myricetin derivatives containing a quinazolinone moiety. ACS Omega. 2021;6:30826–33. [DOI] [PubMed] [PMC]

29.

Titford M. The long history of hematoxylin. Biotech Histochem. 2005;80:73–8. [DOI] [PubMed]

30.

Ali FR, Orchard GE, Mallipeddi R. Hematoxylin in history—the heritage of histology. JAMA Dermatol. 2017;153:328. [DOI] [PubMed]

31.

Chacko SM, Thambi PT, Kuttan R, Nishigaki I. Beneficial effects of green tea: a literature review. Chin Med. 2010;5:13. [DOI] [PubMed] [PMC]

32.

Tan H, Hu Y, Jadhav P, Tan B, Wang J. Progress and challenges in targeting the SARS-CoV-2 papain-like protease. J Med Chem. 2022;65:7561–80. [DOI] [PubMed] [PMC]

33.

Srinivasan V, Brognaro H, Prabhu PR, de Souza EE, Günther S, Reinke PYA, et al. Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease. Commun Biol. 2022;5:805. [DOI] [PubMed] [PMC]

34.

Li L, Ma L, Hu Y, Li X, Yu M, Shang H, et al. Natural biflavones are potent inhibitors against SARS-CoV-2 papain-like protease. Phytochemistry. 2022;193:112984. [DOI] [PubMed] [PMC]

35.

Lewis DSM, Ho J, Wills S, Kawall A, Sharma A, Chavada K, et al. Aloin isoforms (A and B) selectively inhibits proteolytic and deubiquitinating activity of papain like protease (PLpro) of SARS-CoV-2 in vitro. Sci Rep. 2022;12:2145. [DOI] [PubMed] [PMC]

36.

Pendyala B, Patras A, Dash C. Phycobilins as potent food bioactive broad-spectrum inhibitors against proteases of SARS-CoV-2 and other coronaviruses: a preliminary study. Front Microbiol. 2021;12:645713. [DOI] [PubMed] [PMC]

37.

Liu R, Meng C, Zhang Z, Ma H, Lv T, Xie S, et al. Comparative metabolism of schaftoside in healthy and calcium oxalate kidney stone rats by UHPLC-Q-TOF-MS/MS method. Anal Biochem. 2020;597:113673. [DOI] [PubMed]

38.

De Melo GO, Muzitano MF, Legora-Machado A, Almeida TA, De Oliveira DB, Kaiser CR, et al. C-Glycosylflavones from the aerial parts of Eleusine indica inhibit LPS-induced mouse lung inflammation. Planta Med. 2005;71:362–3. [DOI] [PubMed]

39.

Dwivedy A, Mariadasse R, Ahmad M, Chakraborty S, Kar D, Tiwari S, et al. Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2. PLoS Comput Biol. 2021;17:e1009384. [DOI] [PubMed] [PMC]

40.

Masyeni S, Iqhrammullah M, Frediansyah A, Nainu F, Tallei T, Emran TB, et al. Molnupiravir: a lethal mutagenic drug against rapidly mutating severe acute respiratory syndrome coronavirus 2—a narrative review. J Med Virol. 2022;94:3006–16. [DOI] [PubMed] [PMC]

41.

Zandi K, Musall K, Oo A, Cao D, Liang B, Hassandarvish P, et al. Baicalein and baicalin inhibit SARS-CoV-2 RNA-dependent-RNA polymerase. Microorganisms. 2021;9:893. [DOI] [PubMed] [PMC]

42.

Huang S, Liu Y, Zhang Y, Zhang R, Zhu C, Fan L, et al. Baicalein inhibits SARS-CoV-2/VSV replication with interfering mitochondrial oxidative phosphorylation in a mPTP dependent manner. Signal Transduct Target Ther. 2020;5:266. [DOI] [PubMed] [PMC]

43.

Malone B, Urakova N, Snijder EJ, Campbell EA. Structures and functions of coronavirus replication–transcription complexes and their relevance for SARS-CoV-2 drug design. Nat Rev Mol Cell Biol. 2022;23:21–39. [DOI] [PubMed] [PMC]

44.

Corona A, Wycisk K, Talarico C, Manelfi C, Milia J, Cannalire R, et al. Natural compounds inhibit SARS-CoV-2 nsp13 unwinding and ATPase enzyme activities. ACS Pharmacol Transl Sci. 2022;5:226–39. [DOI] [PubMed] [PMC]

45.

Lu L, Peng Y, Yao H, Wang Y, Li J, Yang Y, et al. Punicalagin as an allosteric NSP13 helicase inhibitor potently suppresses SARS-CoV-2 replication in vitro. Antiviral Res. 2022;206:105389. [DOI] [PubMed] [PMC]

46.

Akhter S, Batool AI, Selamoglu Z, Sevindik M, Eman R, Mustaqeem M, et al. Effectiveness of natural antioxidants against SARS-CoV-2? Insights from the in-silico world. Antibiotics. 2021;10:1011. [DOI] [PubMed] [PMC]

47.

Yosri N, Abd El-Wahed AA, Ghonaim R, Khattab OM, Sabry A, Ibrahim MAA, et al. Anti-viral and immunomodulatory properties of propolis: chemical diversity, pharmacological properties, preclinical and clinical applications, and in silico potential against SARS-CoV-2. Foods. 2021;10:1776. [DOI] [PubMed] [PMC]

48.

Okamoto I, Iwaki K, Koya-Miyata S, Tanimoto T, Kohno K, Ikeda M, et al. The flavonoid kaempferol suppresses the graft-versus-host reaction by inhibiting type 1 cytokine production and CD8⁺ T cell engraftment. Clin Immunol. 2002;103:132–44. [DOI] [PubMed]

49.

Khazdair RM, Anaeigoudari A, Agbor GA. Anti-viral and anti-inflammatory effects of kaempferol and quercetin and COVID-2019: a scoping review. Asian Pac J Trop Biomed. 2021;11:327–34. [DOI]

50.

Tatsimo SJ, Tamokou Jde D, Havyarimana L, Csupor D, Forgo P, Hohmann J, et al. Antimicrobial and antioxidant activity of kaempferol rhamnoside derivatives from Bryophyllum pinnatum. BMC Res Notes. 2012;5:158. [DOI] [PubMed] [PMC]

51.

Liu DY, Gao L, Zhang J, Huo XW, Ni H, Cao L. Anti-inflammatory and anti-oxidant effects of licorice flavonoids on ulcerative colitis in mouse model. Chinese Herb Med. 2017;9:358–68. [DOI]

52.

Larue RC, Xing E, Kenney AD, Zhang Y, Tuazon JA, Li J, et al. Rationally designed ACE2-derived peptides inhibit SARS-CoV-2. Bioconjugate Chem. 2020;32:215–23. [DOI] [PubMed] [PMC]

53.

Chaves OA, Lima CR, Fintelman-Rodrigues N, Sacramento CQ, de Freitas CS, Vazquez L, et al. Agathisflavone, a natural biflavonoid that inhibits SARS-CoV-2 replication by targeting its proteases. Int J Biol Macromol. 2022;222:1015–26. [DOI] [PubMed] [PMC]

54.

Power H, Wu J, Turville S, Aggarwal A, Valtchev P, Schindeler A, et al. Virtual screening and in vitro validation of natural compound inhibitors against SARS-CoV-2 spike protein. Bioorg Chem. 2022;119:105574. [DOI] [PubMed] [PMC]

55.

Gao J, Ding Y, Wang Y, Liang P, Zhang L, Liu R. Oroxylin A is a severe acute respiratory syndrome coronavirus 2-spiked pseudotyped virus blocker obtained from Radix Scutellariae using angiotensin-converting enzyme II/cell membrane chromatography. Phytother Res. 2021;35:3194–204. [DOI] [PubMed] [PMC]

56.

Yang C, Pan X, Xu X, Cheng C, Huang Y, Li L, et al. Salvianolic acid C potently inhibits SARS-CoV-2 infection by blocking the formation of six-helix bundle core of spike protein. Signal Transduct Target Ther. 2020;5:220. [DOI] [PubMed] [PMC]

57.

Chen GY, Pan YC, Wu TY, Yao TY, Wang WJ, Shen WJ, et al. Potential natural products that target the SARS-CoV-2 spike protein identified by structure-based virtual screening, isothermal titration calorimetry and lentivirus particles pseudotyped (Vpp) infection assay. J Tradit Complement Med. 2022;12:73–89. [DOI] [PubMed] [PMC]

58.

Zhou H, Li J, Sun F, Wang F, Li M, Dong Y, et al. A review on recent advances in aloperine research: pharmacological activities and underlying biological mechanisms. Front Pharmacol. 2020;11:538137. [DOI] [PubMed] [PMC]

59.

Bailly C. Cepharanthine: an update of its mode of action, pharmacological properties and medical applications. Phytomedicine. 2019;62:152956. [DOI] [PubMed] [PMC]

60.

Wang X, Li X, Xia Y, Wang D, Li X, Liu L, et al. Hernandezine regulates proliferation and autophagy-induced apoptosis in melanoma cells. J Nat Prod. 2022;85:1351–62. [DOI] [PubMed]

61.

Bai J, Zhang S, Cao J, Sun H, Mang Z, Shen WL, et al. Hernandezine, a natural herbal alkaloid, ameliorates type 2 diabetes by activating AMPK in two mouse models. Phytomedicine. 2022;105:154366. [DOI] [PubMed]

62.

Li P, Li X, Wu Y, Li M, Wang X. A novel AMPK activator hernandezine inhibits LPS-induced TNFα production. Oncotarget. 2017;8:67218–26. [DOI] [PubMed] [PMC]

63.

Farooqi AA, Wen R, Attar R, Taverna S, Butt G, Xu B. Regulation of cell-signaling pathways by berbamine in different cancers. Int J Mol Sci. 2022;23:2758. [DOI] [PubMed] [PMC]

64.

Mokhber-Dezfuli N, Saeidnia S, Gohari AR, Kurepaz-Mahmoodabadi M. Phytochemistry and pharmacology of berberis species. Pharmacogn Rev. 2014;8:8–15. [DOI] [PubMed] [PMC]

65.

Zarei A, Changizi-Ashtiyani S, Taheri S, Ramezani M. A quick overview on some aspects of endocrinological and therapeutic effects of Berberis vulgaris L. Avicenna J Phytomed. 2015;5:485–97. [PubMed] [PMC]

66.

Zupin L, Fontana F, Gratton R, Milani M, Clemente L, Pascolo L, et al. SARS-CoV-2 short-time infection produces relevant cytopathic effects in Vero E6 cell line. Int J Environ Res Public Health. 2021;18:9020. [DOI] [PubMed] [PMC]

67.

Leal CM, Leitão SG, Sausset R, Mendonça SC, Nascimento PHA, de Araujo R Cheohen CF, et al. Flavonoids from Siparuna cristata as potential inhibitors of SARS-CoV-2 replication. Rev Bras Farmacogn. 2021;31:658–66. [DOI] [PubMed] [PMC]

68.

ElNaggar MH, Abdelwahab GM, Kutkat O, GabAllah M, Ali MA, El-Metwally MEA, et al. Aurasperone A inhibits SARS CoV-2 in vitro: an integrated in vitro and in silico study. Mar Drugs. 2022;20:179. [DOI] [PubMed] [PMC]

69.

Gangadevi S, Badavath VN, Thakur A, Yin N, De Jonghe S, Acevedo O, et al. Kobophenol A inhibits binding of host ACE2 receptor with spike RBD domain of SARS-CoV-2, a lead compound for blocking COVID-19. J Phys Chem Lett. 2021;12:1793–802. [DOI] [PubMed] [PMC]

70.

Gowda P, Patrick S, Joshi SD, Kumawat RK, Sen E. Glycyrrhizin prevents SARS-CoV-2 S1 and Orf3a induced high mobility group box 1 (HMGB1) release and inhibits viral replication. Cytokine. 2021;142:155496. [DOI] [PubMed] [PMC]

71.

Fan H, He ST, Han P, Hong B, Liu K, Li M, et al. Cepharanthine: a promising old drug against SARS-CoV-2. Adv Biol (Weinh). 2022;6:e2200148. [DOI] [PubMed] [PMC]

72.

Alhadrami HA, Sayed AM, Hassan HM, Rateb ME. Aloin A inhibits SARS CoV-2 replication by targeting its binding with ACE2 - evidence from modeling-supported molecular dynamics simulation. J Biomol Struct Dyn. 2023:1–10. [DOI] [PubMed]

73.

Venusova E, Kolesarova A, Horky P, Slama P. Physiological and immune functions of punicalagin. Nutrients. 2021;13:2150. [DOI] [PubMed] [PMC]

74.

Xiao J, Chen S, Chen Y, Su J. The potential health benefits of aloin from genus Aloe. Phytother Res. 2022;36:873–90. [DOI] [PubMed]

75.

Baczenas JJ, Andersen H, Rashid S, Yarmosh D, Puthuveetil N, Parker M, et al. Propagation of SARS-CoV-2 in Calu-3 cells to eliminate mutations in the furin cleavage site of spike. Viruses. 2021;13:2434. [DOI] [PubMed] [PMC]

76.

Chaves OA, Fintelman-Rodrigues N, Wang X, Sacramento CQ, Temerozo JR, Ferreira AC, et al. Commercially available flavonols are better SARS-CoV-2 inhibitors than isoflavone and flavones. Viruses. 2022;14:1458. [DOI] [PubMed] [PMC]

77.

Chhetri BK, Tedbury PR, Sweeney-Jones AM, Mani L, Soapi K, Manfredi C, et al. Marine natural products as leads against SARS-CoV-2 infection. J Nat Prod. 2022;85:657–65. [DOI] [PubMed] [PMC]

78.

Park HH, Lee S, Oh JM, Lee MS, Yoon KH, Park BH, et al. Anti-inflammatory activity of fisetin in human mast cells (HMC-1). Pharmacol Res. 2007;55:31–7. [DOI] [PubMed]

79.

Grynkiewicz G, Demchuk OM. New perspectives for fisetin. Front Chem. 2019;7:697. [DOI] [PubMed] [PMC]

80.

Lu TM, Ko HH, Ng LT, Hsieh YP. Free‐radical‐scavenging, antityrosinase, and cellular melanogenesis inhibitory activities of synthetic isoflavones. Chem Biodivers. 2015;12:963–79. [DOI] [PubMed]

81.

Lee AV, Oesterreich S, Davidson NE. MCF-7 cells—changing the course of breast cancer research and care for 45 years. J Natl Cancer Inst. 2015;107:djv073. [DOI] [PubMed]

82.

Bartolomeo CS, Lemes RMR, Morais RL, Pereria GC, Nunes TA, Costa AJ, et al. SARS-CoV-2 infection and replication kinetics in different human cell types: the role of autophagy, cellular metabolism and ACE2 expression. Life Sci. 20221;308:120930. [DOI] [PubMed] [PMC]

83.

Kumar V, Dhanjal JK, Bhargava P, Kaul A, Wang J, Zhang H, et al. Withanone and Withaferin-A are predicted to interact with transmembrane protease serine 2 (TMPRSS2) and block entry of SARS-CoV-2 into cells. J Biomol Struct Dyn. 2022;40:1–13. [DOI] [PubMed] [PMC]

84.

Tolba MF, Omar HA, Azab SS, Khalifa AE, Abdel-Naim AB, Abdel-Rahman SZ. Caffeic acid phenethyl ester: a review of its antioxidant activity, protective effects against ischemia-reperfusion injury and drug adverse reactions. Crit Rev Food Sci Nutr. 2016;56:2183–90. [DOI] [PubMed]

85.

Russo A, Longo R, Vanella A. Antioxidant activity of propolis: role of caffeic acid phenethyl ester and galangin. Fitoterapia. 2002;73:S21–9. [DOI] [PubMed]

86.

Lv L, Cui H, Ma Z, Liu X, Yang L. Recent progresses in the pharmacological activities of caffeic acid phenethyl ester. Naunyn Schmiedebergs Arch Pharmacol. 2021;394:1327–39. [DOI] [PubMed]

87.

Chinese Clinical Trial Registry (ChiCTR) [Internet]. Chinese Clinical Trial Register; c2022 [cited 2022 Oct 4]. Available from: https://www.chictr.org.cn/aboutEN.html

88.

CANnabiDiol for CoviD-19 pATiEnts with mild to moderate symptoms (CANDIDATE) [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04467918

89.

Effect of combined use of ivermectin and colchicine in COVID-19 patients [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT05246072

90.

Effectiveness of colchicine among patients with COVID-19 infection [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04867226

91.

RBR-8jyhxh clinical trial for the treatment of COVID-19 with chloroquine and colchicine [Internet]. The Brazilian Registry of Clinical Trials; [cited 2022 Oct 4]. Available from: https://ensaiosclinicos.gov.br/rg/RBR-8jyhxh/

92.

Effect of colchicine in treatment of COVID-19 [Internet]. World Health Organization; c2022 [cited 2022 Oct 4]. Available from: https://trialsearch.who.int/Trial2.aspx?TrialID=IRCT20190810044500N5

93.

Effect of nanocurcumin supplementation on the severity of symptoms and length of hospital stay in patients with COVID-19 [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://en.irct.ir/trial/51310

94.

Effects of nano curcumin supplementation on the reduction of inflammation and mortality in patients with coronavirus 2019 admitted to ICU ward of Imam Reza hospital in Tabriz [Internet]. Iranian Registry of Clinical Trials riz; c2022 [cited 2022 Oct 4]. Available from: https://www.irct.ir/trial/46712

95.

Evaluation of SinaCurcumin as a complementary therapy in mild to moderate COVID-19: an open label non-randomized clinical trial [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://en.irct.ir/trial/47061

96.

Evaluation of the effect of nano micelles containing curcumin (Sina Ccurcumin) as a therapeutic supplement in patients with COVID-19 and investigating of immune responses balance changes following treatment: a randomized double blind clinical trial [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://www.irct.ir/trial/48843

97.

Evaluation the anti-inflammatory effects of curcumin in the treatment of patients with COVID-19 [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://en.irct.ir/trial/48292

98.

Nutritional supplementation of flavonoids quercetin and curcumin for early mild symptoms of COVID-19 [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT05130671

99.

Effect of nutritional supplement made from Haldi and Black Pepper to prevent and treat active corona virus infection [Internet]. CTRI; [cited 2022 Oct 4]. Available from: https://trialsearch.who.int/Trial2.aspx?TrialID=CTRI%2F2020%2F05%2F025482

100.

Complementary intervention for COVID-19 [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04487964

101.

The effect of Aftogel strips on results of nasopharyngeal secretion PCR test in volunteers with positive test for COVID-19 virus [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://www.irct.ir/trial/51774

102.

Investigating the effectiveness of the use of hesperidin on the clinical conditions of patients with the new coronavirus (SARS-COV-2) [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://www.irct.ir/trial/49150

103.

Study of hesperidin therapy on COVID-19 symptoms (HESPERIDIN) (Hesperidin) [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04715932

104.

Trial to determine the efficacy/safety of plitidepsin vs control in patients with moderate COVID-19 infection (neptuno) [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04784559

105.

Effect of quercetin on prophylaxis and treatment of COVID-19 [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04377789

106.

Evaluation of the effect of quercetin on the effectiveness of antiviral drug regimen in patients with COVID19 [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://en.irct.ir/trial/47396

107.

Quercetin in the prevention of covid-19 infection [Internet]. Clinical Trials Register; c2022 [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT05037240

108.

Can SARS-CoV-2 viral load and COVID-19 disease severity be reduced by resveratrol-assisted zinc therapy (reszinate) [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04542993

109.

Resveratrol and copper for the treatment of COVID-19 pnuemonia [Internet]. Clinical Trials Registry-India; c2022 [cited 2022 Oct 4]. Available from: https://ctri.nic.in/Clinicaltrials/showallp.php?mid1=45115&EncHid=&userName=Rosemarie%20desouza

110.

Randomized proof-of-concept trial to evaluate the safety and explore the effectiveness of resveratrol, a plant polyphenol, for COVID-19 [Internet]. Clinical Trials Registry; [cited 2022 Oct 4]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04400890

111.

Li G, Yuan M, Li H, Deng C, Wang Q, Tang Y, et al. Safety and efficacy of artemisinin-piperaquine for treatment of COVID-19: an open-label, non-randomised and controlled trial. Int J Antimicrob Agents. 2021;57:106216. [DOI] [PubMed] [PMC]

112.

Lin Y, Wu F, Xie Z, Song X, Zhu Q, Wei J, et al. Clinical study of artesunate in the treatment of coronavirus disease 2019. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2020;32:417–20. Chinese. [DOI] [PubMed]

113.

Zhang BY, Chen M, Chen XC, Cao K, You Y, Qian YJ, et al. Berberine reduces circulating inflammatory mediators in patients with severe COVID-19. Br J Surg. 2021;108:e9–11. [DOI] [PubMed] [PMC]

114.

Crippa JAS, Pacheco JC, Zuardi AW, Guimarães FS, Campos AC, Osório FL, et al. Cannabidiol for COVID-19 patients with mild to moderate symptoms (CANDIDATE study): a randomized, double-blind, placebo-controlled clinical trial. Cannabis Cannabinoid Res. 2022;7:658–69. [DOI] [PubMed]

115.

Dorward J, Yu LM, Hayward G, Saville BR, Gbinigie O, Van Hecke O, et al.; PRINCIPLE Trial Collaborative Group PRINCIPLE Trial Collaborative Group. Colchicine for COVID-19 in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial. Br J Gen Pract. 2022;72:e446–55. [DOI] [PubMed] [PMC]

116.

El Sayed RG, Hafez AF, Mohammed Haggag AM, Alhadidy MA. Effect of combined use of ivermectin and colchicine in COVID-19 patients. Egy J Anaesth. 2022;38:365–72. [DOI]

117.

Jalal AM, Aref SF, Albustany DA. Effectiveness of colchicine among patients with COVID-19 infection: a randomized, open-labeled, clinical trial. Indian J Rheumatol. 2022;17:136–41.

118.

Lopes MI, Bonjorno LP, Giannini MC, Amaral NB, Menezes PI, Dib SM, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open. 2021;7:e001455. [DOI] [PubMed] [PMC]

119.

Pourdowlat G, Saghafi F, Mozafari A, Sahebnasagh A, Abedini A, Nabi Meybodi M, et al. Efficacy and safety of colchicine treatment in patients with COVID-19: a prospective, multicenter, randomized clinical trial. Phytother Res. 2022;36:891–8. [DOI] [PubMed]

120.

Sandhu T, Tieng A, Chilimuri S, Franchin G. a case control study to evaluate the impact of colchicine on patients admitted to the hospital with moderate to severe COVID-19 infection. Can J Infect Dis Med Microbiol. 2020;2020:8865954. [DOI] [PubMed] [PMC]

121.

Honarkar Shafie E, Taheri F, Alijani N, Okhovvat AR, Goudarzi R, Borumandnia N, et al. Effect of nanocurcumin supplementation on the severity of symptoms and length of hospital stay in patients with COVID-19: a randomized double-blind placebo-controlled trial. Phytother Res. 2022;36:1013–22. [DOI] [PubMed]

122.

Abbaspour-Aghdam S, Hazrati A, Abdolmohammadi-Vahid S, Tahmasebi S, Mohseni J, Valizadeh H, et al. Immunomodulatory role of nanocurcumin in COVID-19 patients with dropped natural killer cells frequency and function. Eur J Pharmacol. 2022;933:175267. [DOI] [PubMed] [PMC]

123.

Saber-Moghaddam N, Salari S, Hejazi S, Amini M, Taherzadeh Z, Eslami S, et al. Oral nano-curcumin formulation efficacy in management of mild to moderate hospitalized coronavirus disease-19 patients: an open label nonrandomized clinical trial. Phytother Res. 2021;35:2616–23. [DOI] [PubMed]

124.

Hassaniazad M, Eftekhar E, Inchehsablagh BR, Kamali H, Tousi A, Jaafari MR, et al. A triple-blind, placebo-controlled, randomized clinical trial to evaluate the effect of curcumin-containing nanomicelles on cellular immune responses subtypes and clinical outcome in COVID-19 patients. Phytother Res. 2021;35:6417–27. [DOI] [PubMed] [PMC]

125.

Asadirad A, Nashibi R, Khodadadi A, Ghadiri AA, Sadeghi M, Aminian A, et al. Antiinflammatory potential of nano-curcumin as an alternative therapeutic agent for the treatment of mild-to-moderate hospitalized COVID-19 patients in a placebo-controlled clinical trial. Phytother Res. 2022;36:1023–31. [DOI] [PubMed]

126.

Khan A, Iqtadar S, Mumtaz SU, Heinrich M, Pascual-Figal DA, Livingstone S, et al. Oral co-supplementation of curcumin, quercetin, and vitamin d3 as an adjuvant therapy for mild to moderate symptoms of COVID-19—results from a pilot open-label, randomized controlled trial. Front Pharmacol. 2022;13:898062. [DOI] [PubMed] [PMC]

127.

Pawar KS, Mastud RN, Pawar SK, Pawar SS, Bhoite RR, Bhoite RR, et al. Oral curcumin with piperine as adjuvant therapy for the treatment of COVID-19: a randomized clinical trial. Front Pharmacol. 2021;12:669362. [DOI] [PubMed] [PMC]

128.

Gomaa AA, Mohamed HS, Abd-Ellatief RB, Gomaa MA, Hammam DS. Advancing combination treatment with glycyrrhizin and boswellic acids for hospitalized patients with moderate COVID-19 infection: a randomized clinical trial. Inflammopharmacology. 2022;30:477–86. [DOI] [PubMed] [PMC]

129.

Pourahmad M, Shahzamani K, Nikokar F, Saniei M, Saniei M, Soltani R. The effects of licorice mucoadhesive patches on the results of nasopharyngeal swab real-time polymerase chain reaction test of SARS-CoV-2; a randomized triple-blind placebo-controlled clinical trial. Immunopathol Persa. 2022;[Epub ahead of print]. [DOI]

130.

Liao FL, Peng DH, Chen W, Hu HN, Tang P, Liu YY, et al. Evaluation of serum hepatic enzyme activities in different COVID-19 phenotypes. J Med Virol. 2021;93:2365–73. [DOI] [PubMed]

131.

Jahangirifard A, Mirtajani SB, Karimzadeh M, Forouzmehr M, Kiani A, Moradi M, et al. The effect of hesperidin on laboratory parameters of patients with COVID 19: a preliminary report of a clinical trial study. J Iran Med Council. 2022;5:89–95. [DOI]

132.

Dupuis J, Laurin P, Tardif JC, Hausermann L, Rosa C, Guertin MC, et al. Fourteen-day evolution of COVID-19 Symptoms during the third wave in nonvaccinated subjects and effects of hesperidin therapy: a randomized, double-blinded, placebo-controlled study. Evid Based Complement Alternat Med. 2022;2022:3125662. [DOI] [PubMed] [PMC]

133.

D’Ascanio L, Vitelli F, Cingolani C, Maranzano M, Brenner MJ, Di Stadio A. Randomized clinical trial “olfactory dysfunction after COVID-19: olfactory rehabilitation therapy vs. intervention treatment with palmitoylethanolamide and luteolin”: preliminary results. Eur Rev Med Pharmacol Sci. 2021;25:4156–62. [DOI] [PubMed]

134.

De Luca P, Camaioni A, Marra P, Salzano G, Carriere G, Ricciardi L, et al. Effect of ultra-micronized palmitoylethanolamide and luteolin on olfaction and memory in patients with long COVID: results of a longitudinal study. Cells. 2022;11:2552. [DOI] [PubMed] [PMC]

135.

Varona JF, Landete P, Lopez-Martin JA, Estrada V, Paredes R, Guisado-Vasco P, et al. Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19. Life Sci Alliance. 2022;5:e202101200. [DOI] [PubMed] [PMC]

136.

Guisado-Vasco P, González-Cortijo L, D’Errico G, Serrera-Alvarez A, Sotres-Fernandez G, García-Coca M, et al. Plitidepsin for the management of a cancer patient infected with SARS-CoV-2 while receiving chemotherapy. Ann Oncol. 2021;32:1295–7. [DOI] [PubMed] [PMC]

137.

Önal H, Arslan B, Üçüncü Ergun N, Topuz Ş, Yilmaz Semerci S, Kurnaz ME, et al. Treatment of COVID-19 patients with quercetin: a prospective, single center, randomized, controlled trial. Turk J Biol. 2021;45:518–29. [DOI] [PubMed] [PMC]

138.

Shohan M, Nashibi R, Mahmoudian-Sani MR, Abolnezhadian F, Ghafourian M, Alavi SM, et al. The therapeutic efficacy of quercetin in combination with antiviral drugs in hospitalized COVID-19 patients: a randomized controlled trial. Eur J Pharmacol. 2022;914:174615. [DOI] [PubMed] [PMC]

139.

Rondanelli M, Perna S, Gasparri C, Petrangolini G, Allegrini P, Cavioni A, et al. Promising effects of 3-month period of Quercetin Phytosome^® supplementation in the prevention of symptomatic COVID-19 disease in healthcare workers: a pilot study. Life (Basel). 2022;12:66. [DOI] [PubMed] [PMC]

140.

Di Pierro F, Iqtadar S, Khan A, Ullah Mumtaz S, Masud Chaudhry M, Bertuccioli A, et al. Potential clinical benefits of quercetin in the early stage of COVID-19: results of a second, pilot, randomized, controlled and open-label clinical trial. Int J Gen Med. 2021;14:2807–16. [DOI] [PubMed] [PMC]

141.

Kaplan HG, Wang K, Reeves KM, Scanlan JM, Nunn CC, Kieper DA, et al. Reszinate—a phase 1/2 randomized clinical trial of zinc and resveratrol utilizing home patient-obtained nasal and saliva viral sampling. Front Drug Discov. 2022;2:910124. [DOI]

142.

Mittra I, de Souza R, Bhadade R, Madke T, Shankpal PD, Joshi M, et al. Resveratrol and copper for treatment of severe COVID-19: an observational study (RESCU 002). medRxiv [Preprint]. 2020 [cited 2020 Jul 21]. Available from: https://www.medrxiv.org/content/10.1101/2020.07.21.20151423v1

143.

McCreary MR, Schnell PM, Rhoda DA. Randomized double-blind placebo-controlled proof-of-concept trial of resveratrol for outpatient treatment of mild coronavirus disease (COVID-19). Sci Rep. 2021;12:10978. [DOI] [PubMed] [PMC]

144.

Rattis BAC, Ramos SG, Celes MRN. Curcumin as a potential treatment for COVID-19. Front Pharmacol. 2021;12:675287. [DOI] [PubMed] [PMC]

145.

Ibrahim MAA, Abdelrahman AHM, Hussien TA, Badr EAA, Mohamed TA, El-Seedi HR, et al. In silico drug discovery of major metabolites from spices as SARS-CoV-2 main protease inhibitors. Comput Biol Med. 2020;126:104046. [DOI] [PubMed] [PMC]

146.

Marín-Palma D, Tabares-Guevara JH, Zapata-Cardona MI, Flórez-Álvarez L, Yepes LM, Rugeles MT, et al. Curcumin inhibits in vitro SARS-CoV-2 infection in Vero E6 cells through multiple antiviral mechanisms. Molecules. 2021;26:6900. [DOI] [PubMed] [PMC]

147.

Bahun M, Jukić M, Oblak D, Kranjc L, Bajc G, Butala M, et al. Inhibition of the SARS-CoV-2 3CL^pro main protease by plant polyphenols. Food Chem. 2022;373:131594. [DOI] [PubMed] [PMC]

148.

Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, et al. Quercetin, Inflammation and Immunity. Nutrients. 2016;8:167. [DOI] [PubMed] [PMC]

149.

Schlesinger N, Firestein BL, Brunetti L. Colchicine in COVID-19: an old drug, new use. Curr Pharmacol Rep. 2020;6:137–45. [DOI] [PubMed] [PMC]

150.

Yu Y, Liu G, Piao M, Lang M, Wang Y, Jin M, et al. Chemical constituents of Polygonum aviculare L. and their chemotaxonomic significance. Biochem Syst Ecol. 2022;105:104529. [DOI]

151.

Zannella C, Giugliano R, Chianese A, Buonocore C, Vitale GA, Sanna G, et al. Antiviral activity of Vitis vinifera leaf extract against SARS-CoV-2 and HSV-1. Viruses. 2021;13:1263. [DOI] [PubMed] [PMC]

152.

Liu S, Wang B, Li XZ, Qi LF, Liang YZ. Preparative separation and purification of liensinine, isoliensinine and neferine from seed embryo of Nelumbo nucifera GAERTN using high-speed counter-current chromatography. J Sep Sci. 2009;32:2476–81. [DOI] [PubMed]

153.

Sanna C, Marengo A, Acquadro S, Caredda A, Lai R, Corona A, et al. In vitro anti-HIV-1 reverse transcriptase and integrase properties of Punica granatum L. leaves, bark, and peel extracts and their main compounds. Plants. 2021;10:2124. [DOI] [PubMed] [PMC]

154.

Pasquereau S, Nehme Z, Haidar Ahmad S, Daouad F, Van Assche J, Wallet C, et al. Resveratrol inhibits HCoV-229E and SARS-CoV-2 coronavirus replication in vitro. Viruses. 2021;13:354. [DOI] [PubMed] [PMC]

155.

de Oliveira JR, Antunes BS, do Nascimento GO, Kawall JCS, Oliveira JVB, Silva KGDS, et al. Antiviral activity of medicinal plant-derived products against SARS-CoV-2. Exp Biol Med (Maywood). 2022;247:1797–809. [DOI] [PubMed]