Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs) are widely used as antidiabetic and anti-obesity agents. Although conventional GLP-1 RAs such as liraglutide and semaglutide are acylated with fatty acids to delay their degradation by dipeptidylpeptidase-4 (DPP-4), the manufacturing process is challenging. We previously developed selectively lipidated GLP-1 peptides at their only tryptophan residue (peptide A having one 8-amino-3,6-dioxaoctanoic acid (miniPEG) linker and peptide B having three miniPEG linkers).
View Article and Find Full Text PDFThe skin is constantly exposed to environmental sensory stimuli, which may include harmful volatiles and small hydrophobic molecules. However, the skin's protective mechanism against the latter agents is unclear. Here, we demonstrate that odorant binding protein 2A (OBP2A) protects epidermal keratinocytes against cytotoxic small hydrophobic molecules.
View Article and Find Full Text PDFBioorg Med Chem Lett
September 2024
For small-molecule drugs, lipidation via a cleavable linkage can extend half-life in circulation through interaction with albumin. Here we modified the cysteinylprolyl ester (CPE) system used in peptide thioester synthesis, which normally requires basic conditions, for use as an self-immolative linker and release device for a lipid-gemcitabine conjugate. To improve release under physiological conditions for medical application, a methyl group at the α-position of cysteine on the CPE unit was incorporated in anticipation of the Thorpe-Ingold effect.
View Article and Find Full Text PDFLate-stage formation of a sactionine thioether bond connecting a Gly α-carbon and Cys thiol was achieved by Lossen rearrangement of a glycyl hydroxamic acid (GlyHA) residue in a peptide. Lossen rearrangement allowed conversion of GlyHA within a peptide to an -acyl iminium equivalent, which subsequently reacted with -acetamidomethyl Cys (Cys(Acm)) in TFA in the presence of guanidine hydrochloride (Gn·HCl) to yield the desired thioether linkage in the final stage.
View Article and Find Full Text PDFAn oxidant-free approach to the synthesis of -glyoxylyl peptides has been developed that utilizes the Lossen rearrangement of the N-terminal glycyl hydroxamic acid residue. The synthesis proceeds via an intramolecular redox mechanism to yield the glyoxylyl peptides, which are then subjected to various peptide cyclization procedures. The reaction scheme is suitable for oxidation-sensitive moieties including amino acids.
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