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<p>Cyclic peptides are an attractive class of bioactive molecules whose proven utility in the research lab and clinic has fueled the development of new candidates with diverse chemical structures and functions. However, these candidates have been largely limited to naturally evolved products or their derivatives. Herein, we describe the <i>de novo</i> discovery of bicyclic peptides using a phage-encoded library of peptides possessing the characteristic framework of naturally occurring α-conotoxins (α-Ctxs). Selection against α7 nicotinic acetylcholine receptor yielded a bicyclic peptide possessing an uncanonical disulfide connectivity rarely found in naturally occurring α-Ctxs. The chemically synthesized analogue of the hit demonstrated a more potent inhibitory effect on the receptor (IC<sub>50</sub> = 8.6 nmol/L) compared to the majority of known natural α-Ctxs. Cryo-EM structural studies revealed that the binding mode of this selected peptide to the receptor differed from that of natural α-Ctxs, based on the orientation of the peptide in the binding pocket and its contacts with the receptor. Our work highlights the utility of a natural toxin-based directed evolution strategy to identify conformationally constrained peptide binders of target proteins, and is expected to accelerate the discovery of well-behaved peptides for use as biological probes and therapeutics.</p>

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De novo discovery of unnatural and potent conotoxin-like bicyclic peptides through a phage-encoded library

  • 期刊论文

  • 发表日期：

    2025年2月25日

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  • Xiuxiu Cao,
  • Haopeng Chen,
  • Xudong Wang,
  • Xichu Yang,
  • Tao Wang,
  • Li Zhou,
  • Chaowei Shi,
  • Sanling Liu,
  • Changlin Tian,
  • Demeng Sun

摘要

Cyclic peptides are an attractive class of bioactive molecules whose proven utility in the research lab and clinic has fueled the development of new candidates with diverse chemical structures and functions. However, these candidates have been largely limited to naturally evolved products or their derivatives. Herein, we describe the de novo discovery of bicyclic peptides using a phage-encoded library of peptides possessing the characteristic framework of naturally occurring α-conotoxins (α-Ctxs). Selection against α7 nicotinic acetylcholine receptor yielded a bicyclic peptide possessing an uncanonical disulfide connectivity rarely found in naturally occurring α-Ctxs. The chemically synthesized analogue of the hit demonstrated a more potent inhibitory effect on the receptor (IC50 = 8.6 nmol/L) compared to the majority of known natural α-Ctxs. Cryo-EM structural studies revealed that the binding mode of this selected peptide to the receptor differed from that of natural α-Ctxs, based on the orientation of the peptide in the binding pocket and its contacts with the receptor. Our work highlights the utility of a natural toxin-based directed evolution strategy to identify conformationally constrained peptide binders of target proteins, and is expected to accelerate the discovery of well-behaved peptides for use as biological probes and therapeutics.