Peptide Synthesis
Breaking the Bottleneck of Cysteine Selective Modification: Triazine-Pyridine Chemistry Enables Precision Protein Coupling
Today we share significant research findings published in Science Advancesby a Chinese scientific team. The study reports a novel cysteine (Cys)-selective bioconjugation technology based on a modular 1,3,5-triazine scaffold—Triazine-Pyridinium Chemistry (TPC). This work addresses the critical need for Cys-selective reagents with higher stability in therapeutic applications such as antibody-drug conjugates (ADCs). Through systematic structural modifications and computational studies, the team optimized a reagent capable of achieving near-quantitative labeling of Cys (>95% yield) under physiological conditions (pH 7.4), while effectively suppressing reactivity towards tyrosine (Tyr), overcoming the limitations of early TPC probes. The study demonstrated its good compatibility with various peptides and proteins, including the therapeutic antibody trastuzumab, and showcased its potential in constructing ADCs. The optimized labeling method ensures excellent stability of the conjugates in biological environments, highlighting the practical application value of this approach.
Additive-Free Peptide Synthesis Using Pentafluorophenyl Esters as the Sequence Oligopeptide Synthesis via a Flow Reaction
Today, we share an important research article published in Organic Process Research & Developmentby the team of Tomohiro Hattori and Hisashi Yamamoto from the Peptide Science Center at Chubu University, Japan. Addressing long-standing challenges in traditional peptide synthesis such as excessive additive use, byproduct generation, and process complexity, this study developed a novel flow chemistry synthesis strategy based on pentafluorophenyl (Pfp) esters. The core of this method lies in leveraging the high reactivity and stability of Pfp esters to achieve efficient, rapid condensation with stoichiometric amino acid esters—including the highly challenging N-methyl amino acid esters—without requiring any additives. The research further established a continuous flow system integrated with a DBU polymer for online deprotection, successfully accomplishing the sequential assembly from dipeptides to pentapeptides (including bioactive sequences like Leu-enkephalin and thymopentin). The products were obtained with high purity, and the system enabled automated, long-duration synthesis on a gram scale. This work provides a brand-new solution for developing green, efficient, and scalable manufacturing processes for peptide pharmaceuticals.
Hydrophobic Tag-Assisted Liquid-Phase Synthesis of Tirzepatide
Today, we share an important research article from the team led by Lin Dong, published in Organic Letters. This work addresses the bottlenecks of high cost and cumbersome procedures in solid-phase peptide synthesis (SPPS) for the peptide drug Tirzepatide (a novel dual-target agonist for treating type 2 diabetes and obesity) by developing a novel hydrophobic tag-assisted liquid-phase peptide synthesis (LPPS) strategy. This method introduces soluble hydrophobic tags (TAGa and TAGb), leveraging their unique solubility properties to achieve efficient separation, significantly reducing amino acid and solvent waste. It also employs a dual-protection (Cbz/Fmoc) strategy on lysine to precisely control side-chain assembly, ultimately successfully synthesizing the 39-amino-acid Tirzepatide with high yield. This work provides a new approach for the green and economical large-scale production of complex peptide drugs.
“Thiol-Ene Photoclick Chemistry for Efficient Bicyclic Peptide Synthesis and Genetically Encoded Peptide Library”
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.
“A Picolyl-Based Cys Caging/Uncaging Strategy Facilitates Protein Synthesis”
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.
“Dual Self-Promoted Ring-Opening Polymerization towards Cationic Polypeptoids with Stable Helices”
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.
"Accurate de novo design of high-affinity protein-binding macrocycles using deep learning"
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.
“Generative latent diffusion language modeling yields anti-infective synthetic 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.
“Discovering highly potent antimicrobial peptides with deep generative model HydrAMP”
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.
"Expanding Peptide Chemical Space via Acid-Mediated Arginine Modification"
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.