2. Academic Validation
  3. A Top-Down Design Approach for Generating a Peptide PROTAC Drug Targeting Androgen Receptor for Androgenetic Alopecia Therapy

A Top-Down Design Approach for Generating a Peptide PROTAC Drug Targeting Androgen Receptor for Androgenetic Alopecia Therapy

  • J Med Chem. 2024 Jun 27;67(12):10336-10349. doi: 10.1021/acs.jmedchem.4c00828.
Bohan Ma 1,  Donghua Liu 1,  Zhe Wang 2,  Dize Zhang 1,  Yanlin Jian 1,  Kun Zhang 3,  Tianyang Zhou 1,  Yibo Gao 1,  Yizeng Fan 1,  Jian Ma 1,  Yang Gao 1,  Yule Chen 1,  Si Chen 4,  Jing Liu 1,  Xiang Li 5,  Lei Li 1
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710049, China.
  • 2 Institute of Bioengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang 310000, China.
  • 3 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710049, China.
  • 4 School of Medicine, Shanghai University, 99 Shangda Road, Shanghai 200444, China.
  • 5 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
PMID: 38836467 DOI: 10.1021/acs.jmedchem.4c00828
Abstract

While large-scale artificial intelligence (AI) models for protein structure prediction and design are advancing rapidly, the translation of deep learning models for practical macromolecular drug development remains limited. This investigation aims to bridge this gap by combining cutting-edge methodologies to create a novel peptide-based PROTAC drug development paradigm. Using ProteinMPNN and RFdiffusion, we identified binding Peptides for Androgen Receptor (AR) and Von Hippel-Lindau (VHL), followed by computational modeling with Alphafold2-multimer and ZDOCK to predict spatial interrelationships. Experimental validation confirmed the designed peptide's binding ability to AR and VHL. Transdermal microneedle patching technology was seamlessly integrated for the peptide PROTAC drug delivery in androgenic alopecia treatment. In summary, our approach provides a generic method for generating peptide PROTACs and offers a practical application for designing potential therapeutic drugs for androgenetic alopecia. This showcases the potential of interdisciplinary approaches in advancing drug development and personalized medicine.

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