Drug design, development and therapy · 2026
Rational Design and Optimization of MCh-AMP1: A Stable α-Helical Antifungal Peptide with Enhanced Activity Against Candida albicans.
СтатьяНазвание и аннотация: Перевод в очереди
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Pooshang Bagheri Kamran, Salehi Zahra, Arablou Mohammad Mahdi, Goudarzi Mehdi, Jahanshiri Zahra, Hasannejad-Asl Behnam, Razzaghi-Abyaneh Mehdi, Seyedjavadi Sima Sadat
Аннотация
PURPOSE: Candida infections, particularly those caused by Candida albicans, are a growing threat to global health, exacerbated by increasing antifungal resistance. Traditional antifungal treatments are becoming increasingly ineffective due to resistance mechanisms, highlighting the need for innovative therapeutic solutions.
METHODS: In this study, we engineered MCh-AMP1-A7, a derivative of the natural antimicrobial peptide MCh-AMP1, through rational design to enhance its antifungal activity, stability, and selectivity. By modifying the alpha-helical structure, amphipathy, and cationicity of the peptide, we significantly improved its antimicrobial potency.
RESULTS: MCh-AMP1-A7 showed a marked reduction in minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) compared with the parent peptide. Against C. albicans ATCC 10231, the MIC decreased from 16 μg/mL for MCh-AMP1 to 8 μg/mL for MCh-AMP1-A7. Similarly, for clinical isolates of C. glabrata and the reference strain C. krusei DSM 70079, MCh-AMP1-A7 showed a 2- to 4-fold reduction in MIC values, indicating increased potency. This peptide also showed remarkable stability over a wide range of temperature (10-70°C) and pH conditions (pH 2-12), and retained significant antifungal activity even at very high pH values, where the parent peptide would lose much of its potency. Furthermore, MCh-AMP1-A7 displayed an improved in vitro selectivity profile, with a higher lower-bound therapeutic index (>14.5) compared with MCh-AMP1 (>5.9), together with reduced hemolytic activity and lower cytotoxicity against human embryonic kidney cells (HEK293). Molecular docking and molecular dynamics simulations showed that MCh-AMP1-A7 interacts effectively with fungal membranes, with high affinity (ΔG = -8.8 kcal/mol), supporting a membrane-associated mechanism of action.
DISCUSSION: This study provides compelling evidence that MCh-AMP1-A7 is a promising next-generation antifungal agent capable of overcoming the limitations of conventional therapies. The potency, stability, and improved safety profile of the engineered peptide make it a promising candidate for further antifungal development.
METHODS: In this study, we engineered MCh-AMP1-A7, a derivative of the natural antimicrobial peptide MCh-AMP1, through rational design to enhance its antifungal activity, stability, and selectivity. By modifying the alpha-helical structure, amphipathy, and cationicity of the peptide, we significantly improved its antimicrobial potency.
RESULTS: MCh-AMP1-A7 showed a marked reduction in minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) compared with the parent peptide. Against C. albicans ATCC 10231, the MIC decreased from 16 μg/mL for MCh-AMP1 to 8 μg/mL for MCh-AMP1-A7. Similarly, for clinical isolates of C. glabrata and the reference strain C. krusei DSM 70079, MCh-AMP1-A7 showed a 2- to 4-fold reduction in MIC values, indicating increased potency. This peptide also showed remarkable stability over a wide range of temperature (10-70°C) and pH conditions (pH 2-12), and retained significant antifungal activity even at very high pH values, where the parent peptide would lose much of its potency. Furthermore, MCh-AMP1-A7 displayed an improved in vitro selectivity profile, with a higher lower-bound therapeutic index (>14.5) compared with MCh-AMP1 (>5.9), together with reduced hemolytic activity and lower cytotoxicity against human embryonic kidney cells (HEK293). Molecular docking and molecular dynamics simulations showed that MCh-AMP1-A7 interacts effectively with fungal membranes, with high affinity (ΔG = -8.8 kcal/mol), supporting a membrane-associated mechanism of action.
DISCUSSION: This study provides compelling evidence that MCh-AMP1-A7 is a promising next-generation antifungal agent capable of overcoming the limitations of conventional therapies. The potency, stability, and improved safety profile of the engineered peptide make it a promising candidate for further antifungal development.