Computational optimization of a pan-coronavirus fusion inhibitory peptide targeting spike's heptapeptide repeat region  

作　　者：Peixiang Gao Shuo Liu Xiaojing Chi Xinhui Zhang Xiuying Liu Xuehua Yang Huarui Duan Jingya Zhou Weijin Huang Wei Yanag 

机构地区：[1]Key Laboratory of Pathogen Infection Prevention and Control(Ministry of Education),National Institute of Pathogen Biology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 102629,China [2]NHC Key Laboratory of Systems Biology of Pathogens,National Institute of Pathogen Biology,Chinese Academy of Medical Sciences&Peking Union Medical College,Bejing 102629,China [3]Chinese Academy of Medical Sciences&Peking Union Medical College,Bejing 100005,China [4]Division of HIV/AIDS and Sex-Transmited Virus Vaccines,Institute for Biological Product Control,National Insttutes for Food and Drug Control(NIFDC),State Key Laboratory of Drug Regulatory Science,Beijing 102629,China

出　　处：《Biosafety and Health》2025年第1期44-58,共15页生物安全与健康(英文)

基　　金：supported by the National Natural Science Foundation of China(U22A20553 and 82241064);the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-038, 2022-I2M-1-021).

摘　　要：In the past two decades,highly pathogenic coronaviruses(CoVs),such as severe acute respiratory syndrome coronavirus(SARS-CoV),Middle East respiratory syndrome coronavirus(MERS-CoV),and severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),have constituted a grave threat to human health.Broadspectrum anti-CoV fusion inhibitors that target the heptapeptide repeat(HR)region within the S2 subunit of SARS-CoV-2 spike(S)protein exhibit inhibitory activity against various CoVs.In this study,we employed EK1,a fusion inhibitor previously characterized for its broad spectrum and potent antiviral activity,as a scaffold for computational design to enhance its inhibitory potential using the Rosetta software suite.We designed EK1 variants and synthesized two N-terminally extended EK1 elongation peptides,and evaluated their inhibitory activity.The results revealed that the designed peptides enhanced inhibitory activity against diverse CoVs.Structural analysis and molecular dynamics simulations demonstrated that EK1 variants formed more robust interactions with HR1 of SARS-CoV-2,and these interactions were conserved across different CoVs.These findings underscore the utility of computational approaches in optimizing therapeutic peptides.

关 键 词：Coronaviruses(CoVs) Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) Fusion inhibitors Computational design 

分 类 号：R373[医药卫生—病原生物学]