Improving chemical synthesis and the antimicrobial activity of human defensins through disulfide bond engineering of HBD-3

Abstract

Human β-defensins are disulfide-rich peptides that exhibit broad-spectrum antimicrobial activity against bacteria, fungi, and certain viruses, while also exerting immunomodulatory effects. As naturally occurring host defense peptides in the human body, they are less likely to induce adverse immune reactions or toxicity compared to synthetic drugs. Efficient chemical synthesis of cysteine-rich peptides is critical for drug lead optimization studies, yet in many cases is limiting by the low yields of correctly formed disulfide bonds. Herein, we present novel β-defensin 3 analogues with engineered disulfide bonds, designed to simplify and improve oxidative folding while preserving antimicrobial and antifungal activities. Our results suggest that the judicious replacement of cysteine residues with alanines or selenocysteines may facilitate the development of defensin-based drug leads with enhanced pharmacological properties, addressing their therapeutic potential to combat multidrug resistance.