Peptide Synthesis

Today, we share a research article led by Cesar de la Fuente-Nunez's team, published in Cell Biomaterials. This study developed a generative artificial intelligence platform named AMP-Diffusion, which enables the de novodesign of antimicrobial peptides (AMPs) by integrating latent diffusion models and protein language models (pLMs). This work generates functional peptides directly from the ESM-2 embedding space without requiring predefined motifs or structural priors. Experimental validation demonstrated that 76% of the generated peptides exhibit broad-spectrum antimicrobial activity (including against multidrug-resistant bacteria), with in vivoefficacy comparable to standard antibiotics, providing a scalable, rational design tool to address the antibiotic resistance crisis.

Today, we share a research article led by Ewa Szczurek's team, published in Nature Communications. This study developed a deep generative model named HydrAMP, a conditional variational autoencoder (cVAE) that generates novel antimicrobial peptides (AMPs) with high antimicrobial activity by learning continuous low-dimensional representations of peptides. This work is the first to achieve the controllable generation of analogues of known active/inactive peptides, with the exceptional antibacterial effects of the generated peptides validated through wet-lab experiments. It provides a powerful computational design tool to address the global antimicrobial resistance crisis.

Today, we are sharing a research article led by Monika Raj's team, published in Organic Letters. This study developed an acid-mediated, chemoselective method that efficiently converts the guanidino group of arginine in peptides into an amino pyrimidine structure using malonaldehyde (MDA). This strategy not only achieves near-quantitative conversion and excellent chemoselectivity but also enables further late-stage modification to construct imidazo[1,2-a]pyrimidinium salts, significantly enhancing the cell membrane permeability of peptides. It provides a new platform for expanding the chemical space of peptide-based drugs.

Today we are sharing a research article led by Professor Gong Hegui's team, published in the Journal of the American Chemical Society. This study, for the first time, developed a nickel-catalyzed reductive cross-coupling strategy that enables ligand-controlled, stereodivergent vinylation and arylation of the internal α-carbon within peptide backbones. Using readily available racemic α-tosyl glycine (TsG) units as key electrophiles, this work overcomes the bottleneck of difficult stereocontrol in traditional peptide modification, providing a powerful new tool for the late-stage precise functionalization of peptide therapeutics.

Today we are sharing a research article led by Professor Ping Wang's team, published in the Journal of the American Chemical Society. This study developed a novel solid-phase peptide synthesis (SPPS) platform based on Fmoc/pyridinylmethyl (Fmoc/Pic) chemistry. Utilizing visible-light photocatalytic cleavage of C-X (X=O, N, S) bonds, this platform enables efficient and orthogonal deprotection of amino acid side chains under mild, trifluoroacetic acid (TFA)-free conditions, providing a revolutionary solution for sustainable and efficient synthesis of peptide therapeutics.

Today, we are sharing a research article led by Professor Hugh Nakamura from the Hong Kong University of Science and Technology (HKUST), published in Angewandte Chemie International Edition. This study developed an efficient synthetic strategy that integrates electrochemically assisted nickel-catalyzed cross-electrophile coupling with regioselective Larock macrocyclization, successfully constructing the highly strained tyrosine C6–tryptophan C5′ (Tyr C6–Trp C5′) biaryl linkage and accomplishing the total synthesis of micitide 982, a ribosomally synthesized and post-translationally modified peptide (RiPP). This work provides a modular and generalizable approach for synthesizing analogous complex cyclic peptides.

This article aims to analyze the development of peptide synthesis technologies, with a focused review on the origin, core principles, key technical aspects, current challenges, and future trends of SPPS. It is intended to provide comprehensive and in-depth technical reference for researchers and practitioners in the field.

To date, researchers have designed and developed over a hundred structurally diverse amide coupling reagents, significantly advancing the development of peptide synthesis. This article summarizes several commonly used coupling reagents in peptide synthesis.

Introduction to Fmoc Solid-Phase Synthesis

Fmoc solid-phase synthesis was pioneered by Eric Atherton and Bob Sheppard at the University of Cambridge in the late 1970s (systematically refined by Chan and White). Its core methodology employs the Fmoc (9-fluorenylmethoxycarbonyl) group as the α-amino protecting group for amino acids.