A highly potent and stable pan-coronavirus fusion inhibitor as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases  

作　　者：Jie Zhou Wei Xu Zezhong Liu Chao Wang Shuai Xia Qiaoshuai Lan Yanxing Cai Shan Su Jing Pu Lixiao Xing Youhua Xie Lu Lu Shibo Jiang Qian Wang 

机构地区：[1]Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS),School of Basic Medical Sciences and BSL-3 Facility,Shanghai Institute of Infectious Diseases and Biosecurity,Fudan University,Shanghai 200032,China [2]State Key Laboratory of Toxicology and Medical Countermeasures,Beijing Institute of Pharmacology and Toxicology,Beijing 100850,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第4期1652-1661,共10页药学学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(81822045 and 82041036 to Lu Lu,82041025 to Shibo Jiang,21877127 to Chao Wang);the Program of Shanghai Academic/Technology Research Leader(20XD1420300 to Lu Lu,China).

摘　　要：The development of broad-spectrum antivirals against human coronaviruses(HCoVs)is critical to combat the current coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and its variants,as well as future outbreaks of emerging CoVs.We have previously identified a polyethylene glycol-conjugated(PEGylated)lipopeptide,EK1C4,with potent pan-CoV fusion inhibitory activity.However,PEG linkers in peptide or protein drugs may reduce stability or induce anti-PEG antibodies in vivo.Therefore,we herein report the design and synthesis of a series of dePEGylated lipopeptide-based pan-CoV fusion inhibitors featuring the replacement of the PEG linker with amino acids in the heptad repeat 2 C-terminal fragment(HR2-CF)of HCoV-OC43.Among these lipopeptides,EKL1C showed the most potent inhibitory activity against infection by SARS-CoV-2 and its spike(S)mutants,as well as other HCoVs and some bat SARS-related coronaviruses(SARSr-CoVs)tested.The dePEGylated lipopeptide EKL1C exhibited significantly stronger resistance to proteolytic enzymes,better metabolic stability in mouse serum,higher thermostability than the PEGylated lipopeptide EK1C4,suggesting that EKL1C could be further developed as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases.

关 键 词：CORONAVIRUS LIPOPEPTIDE SARS-CoV-2 Polyethylene glycol Fusion inhibitor 

分 类 号：R914[医药卫生—药物化学]