Cyclophane-containing peptides comprise an important group of macrocyclic peptides with unique structural properties and pharmaceutical relevance. Darobactin A is a ribosomally synthesized and post-translationally modified peptide (RiPP) antibiotic, which features an unusual biscyclophane moiety formed via the class-defining ether crosslink in addition to a carbon-carbon (C-C) crosslink. Because darobactin-like peptides (daropeptides) are widespread in nature, further exploration of these emerging RiPP natural products featuring ether crosslinked cyclophane could facilitate the discovery and development of new bioactive peptides. This perspective provides updated insights into the biosynthesis and classification of daropeptides, highlighting the potential to manipulate daropeptide maturases to access novel bioactive peptide cyclophanes.

Protein-protein interactions (PPIs) impersonate a significant role in many biological processes and are potential therapeutic targets in numerous human diseases. Stapled peptides, as the most promising therapeutic candidate for interfering with PPIs, have a higher degree of α-helicity, improved binding affinity, more resistance to proteolytic digestion, longer serum half-life, and enhanced cell permeability, which exhibits higher pharmacological activity compared with small molecule drugs and biologics. This review outlined the continuous progress of stapled peptides mainly concerning the design principle, structural stability, bioactivity, cell permeability, and potential applications in therapeutics, which is aimed at providing a broad reference for the design and exploration of stapled peptides with enhanced biological and pharmacokinetic properties as the next-generation therapeutic peptide drugs targeting various diseases.

Protein therapeutics are extensively used in the treatment of autoimmune diseases, but a subset of patients appears to be refractory to these treatments, mainly due to the development of an immune response to the drug. A better understanding of the mechanism underlying the therapeutic drug’s failure becomes fundamental for the development of new and more effective treatments. Unfortunately, there are few cases where the exact mechanisms through which drugs bypass immunological tolerance and provoke immunogenicity have been studied. In this context, peptide epitope identification gained increasing importance in investigating the molecular mechanism of therapeutic drug’s immune responses. Despite peptide identification and use to monitor anti-drug antibody (ADA) profiles is a promising research field, their use is far away from a wide application both at the research and at the commercial level. Herein it is reported a compilation of studies in which peptides are directly involved in anti-drug immune responses, becoming the molecular key step for a better understanding of refractory reactions in therapeutic drugs. An overview on T-cell and B-cell peptide recognition is given, showing the growing potential and advantages of peptides when used in the field of refractoriness to drugs. This review includes studies describing antigenic peptides that enable enhanced ADA detection directly in patients’ sera, as well as the proof of concept that asses the use of peptides instead of proteins, to facilitate the identification of neutralizing ADA.

It is widely acknowledged that sialyl Lewis X (sLeX), the composition and linkage of which are N-acetylneuraminic acid (Neu5Ac) α2-3 galactose (Gal) β1-4 [fucose (Fuc) α1-3] N-acetylglucosamine, is usually attached to the cell surface. It presents as a terminal structure on either glycoproteins or glycolipids and has been demonstrated to be related to various biological processes, such as fertilization and selectin binding. Due to the vital role of sLeX, its synthesis as well as its determination approaches have attracted considerable attention from many researchers. In this review, the focus is sLeX on glycoproteins. The biological importance of sLeX in fertilization and development, immunity, cancers, and other aspects will be first introduced. Then the chemical and enzymatic synthesis of sLeX including the contributions from more than 15 international research groups will be described, followed by a brief view of the sLeX detection focusing on monosaccharides and linkages. This review is valuable for those readers who are interested in the chemistry and biology of sLeX.