Deep-Learning-Based Approaches for Rational Design of Stapled Peptides With High Antimicrobial Activity and Stability

Antimicrobial peptides (AMPs) face stability and toxicity challenges in clinical use. Stapled modification enhances their stability and effectiveness, but its application in peptide design is rarely reported. This study built ten prediction models for stapled AMPs using deep and machine learning, tested their accuracy with an independent data set and wet lab experiments, and characterised stapled loop structures using structural, sequence and amino acid descriptors. AlphaFold improved stapled peptide structure prediction. The support vector machine model performed best, while two deep learning models achieved the highest accuracy of 1.0 on an external test set. Designed cysteine- and lysine-stapled peptides inhibited various bacteria with low concentrations and showed good serum stability and low haemolytic activity. This study highlights the potential of the deep learning method in peptide modification and design.