N-terminal acetylation of antimicrobial peptide L163 improves its stability against protease degradation,Journal of Peptide Science

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N-terminal acetylation of antimicrobial peptide L163 improves its stability against protease degradation
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2021-05-13 , DOI: 10.1002/psc.3337
Dandan Li ₁ , Yanhui Yang ₁ , Ruifang Li ₁ , Liang Huang ₁ , Zichao Wang ₁ , Qiwu Deng ₂ , Shuaibo Dong ₂

Affiliation

Antimicrobial peptide L163 was computationally designed by our laboratory; L163 is active against multidrug-resistant (MDR) bacteria but is easily degraded in the plasma and by trypsin. Amino acid substitution, cyclization, and amino-terminal (N-terminal) acetylation were performed to obtain L163 analogs with high stability in the plasma and in trypsin solutions. The stability, antimicrobial activity, and biosafety of L163 and its analogs were investigated. Comparison with unmodified L163 indicated that N-terminal acetylation enhanced the stability against pH, plasma, and trypsin degradation, and phenylalanine (Phe) substitution for leucine (Leu) and cysteine bridge (S–S) cyclization decreased the stability. N-terminal acetylation also enhanced antimicrobial activity against MDR Streptococcus Sc181, Listeria monocytogenes, and Enterococcus E1478F; did not change the activity against MDR Staphylococcus aureus 9, Staphylococcus sciuri P254, and Staphylococcus aureus RN4220; and decreased the activity against Candida tropicalis, Candida albicans, and Enterococcus faecalis Fbc35. Phe substitution for Leu and S–S cyclization decreased the antimicrobial activity. The negative effect of these modifications was detected against biofilm formation by the tested microbial strains. Comparison of Phe substitution for Leu and S–S cyclization indicated that N-terminally acetylated L163 (L163-Ac) is the best candidate. L163-Ac peptide had the highest antibacterial activity and enhanced tolerance to temperature, pH, plasma, and trypsin and low toxicity.

中文翻译：

抗菌肽 L163 的 N 端乙酰化提高了其对蛋白酶降解的稳定性

抗菌肽L163由我们实验室计算设计；L163 对多重耐药 (MDR) 细菌有活性，但很容易在血浆中和被胰蛋白酶降解。进行氨基酸取代、环化和氨基末端（N末端）乙酰化以获得在血浆和胰蛋白酶溶液中具有高稳定性的L163类似物。研究了 L163 及其类似物的稳定性、抗菌活性和生物安全性。与未修饰的 L163 的比较表明，N 末端乙酰化增强了对 pH、血浆和胰蛋白酶降解的稳定性，而苯丙氨酸 (Phe) 取代亮氨酸 (Leu) 和半胱氨酸桥 (S-S) 环化降低了稳定性。N-末端乙酰化还增强了对 MDR链球菌Sc181 的抗菌活性，单核细胞增生李斯特菌和肠球菌E1478F；没有改变对 MDR金黄色葡萄球菌9、Staphylococcus sciuri P254 和金黄色葡萄球菌RN4220 的活性；并降低对热带念珠菌、白色念珠菌和粪肠球菌的活性FB35。Phe 取代 Leu 和 S-S 环化降低了抗菌活性。通过测试的微生物菌株检测到这些修饰对生物膜形成的负面影响。比较 Phe 取代 Leu 和 S-S 环化表明 N-末端乙酰化 L163 (L163-Ac) 是最佳候选者。L163-Ac肽具有最高的抗菌活性和增强的对温度、pH、血浆和胰蛋白酶的耐受性和低毒性。

更新日期：2021-05-13

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