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
{"title":"Exploring the Sequence Space of Antimicrobial Peptide Dendrimers","authors":"Xingguang Cai,&nbsp;Alice Capecchi,&nbsp;Basak Olcay,&nbsp;Markus Orsi,&nbsp;Sacha Javor,&nbsp;Jean-Louis Reymond","doi":"10.1002/ijch.202300096","DOIUrl":null,"url":null,"abstract":"<p>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 <b>T7</b> with sequence (KL)<sub>8</sub>(<i>K</i>KL)<sub>4</sub>(<i>K</i>KLL)<sub>2</sub><i>K</i>KKL. Our computational approach selected analogues unlikely to emerge from a systematic study, including AMPD <b>X66</b> 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 <i>in vivo</i> studies.</p>","PeriodicalId":14686,"journal":{"name":"Israel Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":2.3000,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijch.202300096","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Israel Journal of Chemistry","FirstCategoryId":"92","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ijch.202300096","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0

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.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
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)
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1