Direct synthesis of unnatural amino acids and modifications of peptides via LADA strategy

Unnatural amino acids(UAAs)have broad applications in pharmaceutical sciences and biological studies.Current synthetic methods for UAAs mainly rely on asymmetric catalysis and often require several steps.There is a lack of direct and simple methods.To address this challenge,we designed the LADA(labeling-activation-desulfurization-addition)strategy:selective labeling and activation of cysteine residues,the photocatalytic desulfurization and the subsequent radical addition to alkenes.Although composed of two steps,it is one-pot synthesis and has advantages such as high functional group tolerance,biocompatible reaction condition,and retained stereochemistry.This highly efficient strategy was successfully applied in the direct synthesis of unnatural amino acids and modifications of peptides with more than 50 examples.

LADA strategy for the synthesis of unnatural amino acids and direct modifications of peptides

Unnatural amino acids(UAAs)are important building blocks in organic synthesis and drug discovery.They are also frequently integrated into peptides or proteins for biological studies.However,the direct and simplified synthesis of UAAs remains a great challenge.At the same time,vast known peptide modifications are based on carbon-heteroatom bonds.There are no general methods for peptide modifications via the construction of C–C bonds.To address this challenge,herein we propose the LADA strategy,which is composed of two steps:the selective labeling and activation of cysteine residues,the desulfurization to generate carbon-centered radical and the radical addition to alkenes to build C–C bond.This one-pot protocol has obvious advantages such as good functional group tolerance,biocompatible reaction conditions,and retained stereochemistry.This strategy was successfully utilized for the synthesis of unnatural amino acids and direct modifications of peptides.

Dimethyl Sulfoxide/Visible-Light Comediated Chemoselective C-S Bond Formation Between Tryptophans and Thiophenols Enables Site-Selective Functionalization of Peptides

Late-stage peptide modification showcases a huge potential for the construction of peptide libraries,and the investigation of structure-activity relationships.Herein we report a dimethyl sulfoxide/visible light comediated chemoselective modification of tryptophan residue by forging the C-S structure using thiophenols irradiated with blue light-emitting diodes at room temperature.This method shows excellent chemoselectivity toward the C-2 position of the tryptophan residue and good compatibility with diverse thiophenol derivatives bearing various functional groups.Both protected oligopeptides and unmasked bioactive peptides smoothly underwent site-selective modification,furnishing the corresponding products.Above all,this study provides a new competent toolkit for late-stage peptide modification,labelling,and peptide-drug conjugation and provides a clue for protein bioconjugation.

Postassembly Modifications of Peptides via Metal-Catalyzed C–H Functionalization

The growing importance of peptides and proteins in therapeutic and biomedical applications has provided immense motivation toward the development of new ways to construct and transform peptide molecules.As in other areas of organic synthesis,C–H functionalization(CHF)chemistry could potentially exemplify disruptive technologies for peptide engineering.Over the past decade,the field has witnessed an exciting surge of reports of various metal-catalyzed CHF chemistry for postassembly modification of peptides and proteins.This review chronicles present advances in this research area up to June 2020.The content is organized based on the location of CHF on peptides:amino acid side chains(aromatic and nonaromatic),backbone,and appendant groups on peptide terminus.In addition to the reaction mechanisms of the metal-catalyzed CHF chemistry used in these peptide modification protocols,brief comments on the corresponding nonmetal-mediated strategies are included to provide readers a broad view of the current status of CHF-enabled peptide modification.

Selective N-terminal modification of peptides and proteins:Recent progresses and applications

Numerous strategies for linking desired chemical probes with target peptides and proteins have been developed and applied in the field of biological chemistry.Approaches for site-specific modification of native amino acid residues in test tubes and biological contexts represent novel biological tools for understanding the role of peptides and proteins.Selective N-terminal modification strategies have been broadly studied especially in the last 10 years,as N-terminal positions are typically solvent exposed and provide chemically distinct sites for many peptide and protein targets,making N terminus distinct from other functional groups.A growing number of chemical and enzymatic techniques have been developed to modify N-terminal amino acids,and those techniques have the potential in the fields of medicine,basic research and applied materials science.This review focuses on appraising modification methodologies with the potential for biological applications from the past 10 years.

Reversibly switching the conformation of short peptide through in-tether chiral sulfonium auxiliary

A chirality induced helicity method has been developed to modulate the peptide＇s biophysical and biochemical properties. We report herein a novel approach for reversibly switching the conformation of short constraint a-helical peptides through alkylation of the in-tether thioether and dealkylation of the chiral sulfonium. This traceless redox sensitive tagging strategy broadened our scope of CIH （chirality induced helicity） strategy and provided a valuable approach to functionalize the peptide tether.