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

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

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

Author: Jie ZHOU ¹ ; Wei XU ¹ ; Zezhong LIU ¹ ; Chao WANG ² ; Shuai XIA ¹ ; Qiaoshuai LAN ¹ ; Yanxing CAI ¹ ; Shan SU ¹ ; Jing PU ¹ ; Lixiao XING ¹ ; Youhua XIE ¹ ; Lu LU ¹ ; Shibo JIANG ¹ ; Qian WANG ¹
Author Information

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.
Publication Type:Journal Article
Keywords: Coronavirus; Fusion inhibitor; Lipopeptide; Polyethylene glycol; SARS-CoV-2
From: Acta Pharmaceutica Sinica B 2022;12(4):1652-1661
CountryChina
Language:English
Abstract: 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.