Exploring the Sequence Space of Antimicrobial Peptide Dendrimers

IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Israel Journal of Chemistry Pub Date : 2023-09-11 DOI:10.1002/ijch.202300096
Xingguang Cai, Alice Capecchi, Basak Olcay, Markus Orsi, Sacha Javor, Jean-Louis Reymond
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Abstract

There is an urgent need to develop new antibacterial agents against multidrug resistant bacteria. Herein we report our investigation of antimicrobial peptide dendrimers (AMPDs) active against Gram-negative bacteria, whose sequences were designed using a genetic algorithm optimizing molecular similarity to the previously reported AMPD T7 with sequence (KL)8(KKL)4(KKLL)2KKKL. Our computational approach selected analogues unlikely to emerge from a systematic study, including AMPD X66 with a non-conservative Leu→Glu mutation at the dendrimer core which proved compatible with antibacterial effects. Circular dichroism showed that this AMPD is α-helical. Molecular dynamics suggest that its α-helical structure is stabilized by an intramolecular salt bridge involving the core glutamate side chain and a lysine side chain in the dendrimer branches. More substantial variations at the dendrimer core were also tolerated such as the installation of the dianionic pegylated fatty acid side chain of the drug semaglutide potentially useful for in vivo studies.

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抗菌肽树状大分子序列空间的探索
摘要针对多重耐药细菌,迫切需要开发新的抗菌药物。在此,我们报道了对革兰氏阴性细菌具有活性的抗菌肽树状大分子(AMPDs)的研究,其序列采用遗传算法设计,优化了与先前报道的AMPD T7的分子相似性,序列为(KL) 8 (K KL) 4 (K KLL) 2 K KKL。我们的计算方法选择了不太可能从系统研究中出现的类似物,包括AMPD X66,其树突核心具有非保守的Leu→Glu突变,证明其具有抗菌作用。圆二色性表明该AMPD是α‐螺旋形的。分子动力学表明它的α‐螺旋结构是由分子内盐桥稳定的,盐桥包括核心谷氨酸侧链和树突分支上的赖氨酸侧链。在树状大分子核心的更实质性的变化也被容忍,例如安装药物semaglutide的重阴离子聚乙二醇脂肪酸侧链,可能对体内研究有用。
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来源期刊
Israel Journal of Chemistry
Israel Journal of Chemistry 化学-化学综合
CiteScore
6.20
自引率
0.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: The fledgling State of Israel began to publish its scientific activity in 1951 under the general heading of Bulletin of the Research Council of Israel, which quickly split into sections to accommodate various fields in the growing academic community. In 1963, the Bulletin ceased publication and independent journals were born, with Section A becoming the new Israel Journal of Chemistry. The Israel Journal of Chemistry is the official journal of the Israel Chemical Society. Effective from Volume 50 (2010) it is published by Wiley-VCH. The Israel Journal of Chemistry is an international and peer-reviewed publication forum for Special Issues on timely research topics in all fields of chemistry: from biochemistry through organic and inorganic chemistry to polymer, physical and theoretical chemistry, including all interdisciplinary topics. Each topical issue is edited by one or several Guest Editors and primarily contains invited Review articles. Communications and Full Papers may be published occasionally, if they fit with the quality standards of the journal. The publication language is English and the journal is published twelve times a year.
期刊最新文献
Cover Picture: (Isr. J. Chem. 8-9/2024) Special Issue on RNA-Based Catalysts that Revolutionized the Discovery of Bioactive Peptides Hexagonal and Trigonal Quasiperiodic Tilings Breaking the Degeneracy of Sense Codons – How Far Can We Go? Cover Picture: (Isr. J. Chem. 6-7/2024)
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