School of Public Health/Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 561113, China.
Moutai Institute, Renhuai 564507, China.
J Chem Inf Model. 2024 May 27;64(10):4277-4285. doi: 10.1021/acs.jcim.4c00142. Epub 2024 May 14.
Antifungal peptides (AFPs) are emerging as promising candidates for advanced antifungal therapies because of their broad-spectrum efficacy and reduced resistance development. design of AFPs, however, remains challenging, due to the lack of an efficient and well-validated quantitative assessment of antifungal activity. This study introduced an AFP design approach that leverages an innovative quantitative metric, named the antifungal index (AFI), through a three-step process, , segmentation, single-point mutation, and global multipoint optimization. An exhaustive search of 100 putative AFP sequences indicated that random modifications without guidance only have a 5.97-20.24% chance of enhancing antifungal activity. Analysis of the search results revealed that (1) N-terminus truncation is more effective in enhancing antifungal activity than the modifications at the C-terminus or both ends, (2) introducing the amino acids within the 10-60% sequence region that enhance aromaticity and hydrophobicity are more effective in increasing antifungal efficacy, and (3) incorporating alanine, cysteine, and phenylalanine during multiple point mutations has a synergistic effect on enhancing antifungal activity. Subsequently, 28 designed peptides were synthesized and tested against four typical fungal strains. The success rate for developing promising AFPs, with a minimal inhibitory concentration of ≤5.00 μM, was an impressive 82.14%. The predictive and design tool is accessible at https://antifungipept.chemoinfolab.com.
抗真菌肽（AFPs）作为一种有前途的新型抗真菌治疗方法，由于其广谱疗效和降低耐药性发展的潜力而受到关注。然而，由于缺乏有效的和经过充分验证的定量评估抗真菌活性的方法，AFPs 的设计仍然具有挑战性。本研究通过三步过程，即分割、单点突变和全局多点优化，引入了一种利用创新定量指标 - 抗真菌指数（AFI）的 AFP 设计方法。对 100 个假定的 AFP 序列进行的详尽搜索表明，没有指导的随机修饰只有 5.97-20.24%的机会提高抗真菌活性。对搜索结果的分析表明：（1）与 C 末端或两端的修饰相比，N 末端截断更有效地增强抗真菌活性；（2）引入增强芳香性和疏水性的 10-60%序列区域内的氨基酸更有效地提高抗真菌功效；（3）在多点突变过程中结合丙氨酸、半胱氨酸和苯丙氨酸对增强抗真菌活性具有协同作用。随后，合成了 28 个设计肽并对四种典型真菌菌株进行了测试。开发具有最小抑制浓度≤5.00 μM 的有前途的 AFP 的成功率令人印象深刻，达到了 82.14%。预测和设计工具可在 https://antifungipept.chemoinfolab.com 上获得。
