PepScaf: Harnessing Machine Learning with In Vitro Selection toward De Novo Macrocyclic Peptides against IL-17C/IL-17RE Interaction.

Journal: Journal of medicinal chemistry
PMID: 37480587

Abstract

The combination of library-based screening and artificial intelligence (AI) has been accelerating the discovery and optimization of hit ligands. However, the potential of AI to assist in de novo macrocyclic peptide ligand discovery has yet to be fully explored. In this study, an integrated AI framework called PepScaf was developed to extract the critical scaffold relative to bioactivity based on a vast dataset from an initial in vitro selection campaign against a model protein target, interleukin-17C (IL-17C). Taking the generated scaffold, a focused macrocyclic peptide library was rationally constructed to target IL-17C, yielding over 20 potent peptides that effectively inhibited IL-17C/IL-17RE interaction. Notably, the top two peptides displayed exceptional potency with IC values of 1.4 nM. This approach presents a viable methodology for more efficient macrocyclic peptide discovery, offering potential time and cost savings. Additionally, this is also the first report regarding the discovery of macrocyclic peptides against IL-17C/IL-17RE interaction.

Authors

  • Silong Zhai
    School of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
  • Yahong Tan
    State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, China.
  • Chengyun Zhang
    Artificial Intelligent Aided Drug Discovery Lab, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China.
  • Christopher John Hipolito
    Screening & Compound Profiling, Quantitative Biosciences, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
  • Lulu Song
    Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China.
  • Cheng Zhu
    Translational Sciences, Sanofi US, Framingham, MA, 01701, USA. Cheng.Zhu@sanofi.com.
  • Youming Zhang
    Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, PR China.
  • Hongliang Duan
    Artificial Intelligent Aided Drug Discovery Lab, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China.
  • Yizhen Yin
    State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, China.

Keywords

External Resources

Popular Topics
Recent Journals