No abstract is available for this article.

ABSTRACTThe constrained tryptophan (Trp) analog 1,2,3,4‐tetrahydro‐β‐carboline‐3‐carboxylic acid (Tcc) is used to restrict peptide conformation in structure–activity relationship studies. Although Pictet–Spengler cyclization of Trp and aldehydes with mineral acid gives Tcc analogs, such harsh conditions do not tolerate acid‐labile functionality. To enable broader use of Tcc residues, mild conditions are now reported for the on‐resin Pictet–Spengler cyclisation in the presence of acid‐labile side chain protection and linker strategies.

No abstract is available for this article.

No abstract is available for this article.

ABSTRACTMucus is the biological hydrogel that lines the mucosal surfaces of mammals and acts as a protective barrier. Its main proteinaceous component is mucin, the high molecular weight, degree of glycosylation, and hardly uniquely defined nature of which hamper precise structures/property investigations based on biological samples. In contrast, chemically precisely defined peptide model systems inspired by such natural glycoproteins represent synthetically readily obtainable tools with excellent properties for both fundamental research and biomedical applications. Herein, we report the design and characterization of a library of histidine‐ and monosaccharide‐containing coiled coil peptides that form hydrogels to different degrees in the presence of divalent metal ions Cu2+, Zn2+, Ca2+, and Fe2+. Using rheology, circular dichroism, and transmission electron microscopy, we determined the viscoelastic properties and global structures of these glycopeptide materials. This study reflects the interplay between glycan identity, histidine position, and divalent metal ion on the mechanical strength of these hydrogels.

ABSTRACTBioconjugation chemistry is an important tool for studying proteins, developing pharmaceutical agents, and for many other applications. Conventional methods for protein functionalization rely on chemoselective reactions but often have poor regioselectivity. Peptide tags facilitating site‐selective chemical covalent modification of proteins are of great value in the synthesis of protein conjugates. Ideally, a protein would only have to be minimally mutated prior to chemical modification to avoid interfering with native protein folding, trafficking, and function. This short review summarizes the advances in the developments and applications of peptide tags for covalent modifications that proceed without enzymatic assistance.

ABSTRACTAmyloidosis, a self‐assembly of proteins or peptides, is associated with numerous degenerative diseases, such as gelsolin amyloidosis, which remain without a cure. Gelsolin protein is an actin‐binding protein, but when aggregated in a diseased state, it is a potential drug target. Specifically, gelsolin mutations, N184K and D187Y, have been linked to renal amyloidosis and systemic progressive deposition of amyloids, respectively. Understanding how such mutations mitigate gelsolin aggregation and how this process can be prevented through small molecule inhibitors is of interest. Herein, we explored the efficacies of plant‐based naturally occurring cytokinin (CK) molecules as aggregation modulators in vitro. Using various biophysical methods, such as spectroscopy and microscopy, the aggregation of wild‐type gelsolin peptide 184NNGDCFILDL193 and its mutants (N184K, D187Y) was investigated. The mutations significantly promoted aggregation, which is of biological significance. The CK trans‐zeatin (tZ) was a more effective disaggregation promoter compared with kinetin (Kin). The experimentally determined IC50 values were in the 9–20 μM range. The mode of inhibition was identified as direct non‐covalent complexation between the CK and the peptides by using mass spectrometry and molecular docking studies. Data show that CKs are promising amyloid modulators, which can be easily translatable to other amyloid systems.

ABSTRACTThe development of therapeutic small interfering RNAs (siRNAs) has lately gained significant momentum due to their ability to silence genes in a highly specific manner. The main obstacle withholding the wider translation of siRNA‐based drug modalities is their limited half‐life and poor bioavailability, especially in extra‐hepatic tissues. Consequently, various drug delivery systems (DDSs) have been developed to improve the delivery of siRNAs, including short delivery peptides called cell‐penetrating peptides (CPPs). In this study, we explore the potential of using alkenyl‐alanine modifications to enhance the siRNA delivery efficacy with CPPs. We demonstrate on hPep peptides that incorporation of alkenyl‐alanines enhances the encapsulation of siRNAs into stable nanoparticles and contributes to increased cellular uptake. Furthermore, we demonstrate that the lead peptide, hPep3, induces effective RNAi‐mediated gene silencing in a reporter cell model as well as on the disease‐implicated endogenous CD45 gene target. The biodistribution studies in mice show that the alkenyl‐alanines are systemically well tolerated, and employing such modifications in the peptide backbone improves siRNA delivery in several tissues, including extra‐hepatic sites. As demonstrated on hPep peptides, alkenyl‐alanines offer a simple yet robust way to enhance the delivery efficacy of CPPs and have the potential to advance siRNA therapeutics beyond the liver targets.