Computer aided design of CGA-N9 derived peptides based on oligopeptide transporters and their antifungal evaluations

CGA-N9 is an antifungal peptide that primarily targets Candida spp. with a mild activity. Our preceding research confirmed that the CGA-N9 crosses cell membrane with the assistance of C. tropicalis oligopeptide transporter (CtOPT) -1 and - 9. In this study, CGA-N9-derived peptides were designed following the molecular docking results with CtOPT-1 and -9. Compared with CGAN9, they exhibit higher transmembrane efficiency with the assistance of CtOPT-1 during the early phase of transmembrane processes and CtOPT-9 in the late phase. And they displayed significantly enhanced antifungal activity, with lower minimum inhibitory concentrations (MICs) against C. tropicalis, C. albicans, and C. parapsilosis, as well as improved biosafety. Among them, CGAN93 was the most optimizing, with a therapeutic index of 145.33. Furthermore, in a mouse model of systemic candidiasis, CGAN93 demonstrated a therapeutic effect comparable to fluconazole, significantly improving the survival rate of mice, attenuating organ damage, and enhancing the immune organ index. In conclusion, OPTs-based computer aided design is an effective strategy for enhancing the activities of antimicrobial peptides (AMPs) by improving transmembrane transport efficiency. CGAN93 is a promising drug candidate for treating Candidiasis.