Peptide Synthesis

Today, we share with you important research from the team led by Xinxiang Lei of Lanzhou University, published in Angewandte Chemie International Edition. This work marks the first application of thiol-ene photoclick chemistry to the efficient bicyclization of unprotected peptides, developing a rapid, highly selective, and highly biocompatible new method. The researchers ingeniously utilized the inexpensive and readily available tri-alkene crosslinker TAIC. Under visible light activation, cyclization is completed in just 6 minutes. They successfully integrated this with phage display technology to construct a genetically encoded bicyclic peptide library, screening for novel ligands with ultra-high sub-micromolar affinity for the important drug target cyclophilin A. This study provides a powerful and versatile new platform for the discovery of constrained peptide drugs.

Today, we share with you important research led by Professor Ping Wang's team at Shanghai Jiao Tong University, published in Angewandte Chemie International Edition. This study addresses the core challenge of selective protection and deprotection of cysteine (Cys) in protein chemical synthesis, developing a novel picolyl (Pic)-based caging/uncaging strategy. Through simple pH and wavelength control, this work achieves efficient, orthogonal protection of Cys residues. It has been successfully applied to the synthesis of complex proteins such as Interleukin-4 (IL-4) and Tumor Necrosis Factor-α (TNF-α), providing an innovative tool for precise protein modification and synthesis.

Today, we share significant research led by Zhengbiao Zhang's team, published in Angewandte Chemie International Edition. This study successfully synthesized cationic polypeptoid mimics bearing bulky chiral side chains via an innovative dual self-promoted ring-opening polymerization strategy. Contrary to conventional understanding, these cationic polypeptoids not only did not disrupt the helical structure but instead formed exceptionally stable, polyproline type I-like helices. This work challenges the traditional paradigm that "cationic side chains inevitably destabilize helices" and opens new avenues for designing advanced functional polymers combining low toxicity and high cellular uptake efficiency.

Today, we share a research article led by the teams of David Baker and Gaurav Bhardwaj, published in Nature Chemical Biology. This study developed RFpeptides, a denoising diffusion-based generative AI pipeline that enables the de novodesign of macrocyclic peptides by integrating the RoseTTAFold2 (RF2) structure prediction network and the RFdiffusion protein backbone generation framework. This work achieves, for the first time, the precise design of high-affinity macrocyclic peptide binders targeting multiple protein targets, validated by X-ray crystallography showing high agreement between the designed and experimental structures (Cα RMSD < 1.5 Å). It provides a scalable and efficient platform for the rational design of macrocyclic peptides.

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.