1. Discovery of AMPs from random peptides via deep learning-based model and biological activity validation.
- Author
-
Du J, Yang C, Deng Y, Guo H, Gu M, Chen D, Liu X, Huang J, Yan W, and Liu J
- Subjects
- Animals, Mice, Drug Discovery, Humans, Dose-Response Relationship, Drug, Staphylococcal Infections drug therapy, Structure-Activity Relationship, Hemolysis drug effects, Peptides pharmacology, Peptides chemistry, Deep Learning, Microbial Sensitivity Tests, Staphylococcus aureus drug effects, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents chemical synthesis, Antimicrobial Peptides pharmacology, Antimicrobial Peptides chemistry, Antimicrobial Peptides chemical synthesis
- Abstract
The ample peptide field is the best source for discovering clinically available novel antimicrobial peptides (AMPs) to address emerging drug resistance. However, discovering novel AMPs is complex and expensive, representing a major challenge. Recent advances in artificial intelligence (AI) have significantly improved the efficiency of identifying antimicrobial peptides from large libraries, whereas using random peptides as negative data increases the difficulty of discovering antimicrobial peptides from random peptides using discriminative models. In this study, we constructed three multi-discriminator models using deep learning and successfully screened twelve AMPs from a library of 30,000 random peptides. three candidate peptides (P2, P11, and P12) were screened by antimicrobial experiments, and further experiments showed that they not only possessed excellent antimicrobial activity but also had extremely low hemolytic activity. Mechanistic studies showed that these peptides exerted their bactericidal effects through membrane disruption, thus reducing the possibility of bacterial resistance. Notably, peptide 12 (P12) showed significant efficacy in a mouse model of Staphylococcus aureus wound infection with low toxicity to major organs at the highest tested dose (400 mg/kg). These results suggest deep learning-based multi-discriminator models can identify AMPs from random peptides with potential clinical applications., Competing Interests: Declaration of competing interest The authors declare that no known competing financial interests or personal relationships could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF