A novel cyclic γ-AApeptide-based long-acting pan-coronavirus fusion inhibitor with potential oral bioavailability by targeting two sites in spike protein

Songyi Xue; Xinling Wang; Lei Wang; Wei Xu; Shuai Xia; Lujia Sun; Shaohui Wang; Ning Shen; Ziqi Yang; Bo Huang; Sihao Li; Chuanhai Cao; Laurent Calcul; Xingmin Sun; Lu Lu; Jianfeng Cai; Shibo Jiang

doi:10.1038/s41421-022-00455-6

A novel cyclic γ-AApeptide-based long-acting pan-coronavirus fusion inhibitor with potential oral bioavailability by targeting two sites in spike protein

Cell Discov. 2022 Sep 8;8(1):88. doi: 10.1038/s41421-022-00455-6.

Authors

Songyi Xue^#¹, Xinling Wang^#², Lei Wang¹, Wei Xu², Shuai Xia², Lujia Sun², Shaohui Wang³, Ning Shen¹, Ziqi Yang¹, Bo Huang¹, Sihao Li¹, Chuanhai Cao^{1

4}, Laurent Calcul¹, Xingmin Sun³, Lu Lu⁵, Jianfeng Cai⁶, Shibo Jiang⁷

Affiliations

¹ Department of Chemistry, University of South Florida, 4202 E, Fowler Ave., Tampa, FL, USA.
² Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, China.
³ Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
⁴ Department of Pharmaceutical Science, Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA.
⁵ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, China. lul@fudan.edu.cn.
⁶ Department of Chemistry, University of South Florida, 4202 E, Fowler Ave., Tampa, FL, USA. jianfengcai@usf.edu.
⁷ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, China. shibojiang@fudan.edu.cn.

^# Contributed equally.

Abstract

The receptor-binding domain (RBD) in S1 subunit and heptad repeat 1 (HR1) domain in S2 subunit of SARS-CoV-2 spike (S) protein are the targets of neutralizing antibodies (nAbs) and pan-coronavirus (CoV) fusion inhibitory peptides, respectively. However, neither nAb- nor peptide-based drugs can be used orally. In this study, we screened a one-bead-two-compound (OBTC) cyclic γ-AApeptide library against SARS-CoV-2 S protein and identified a hit: S-20 with potent membrane fusion inhibitory activity, but moderate selectivity index (SI). After modification, one derivative, S-20-1, exhibited improved fusion inhibitory activity and SI (>1000). S-20-1 could effectively inhibit infection by pseudotyped and authentic SARS-CoV-2 and pseudotyped variants of concern (VOCs), including B.1.617.2 (Delta) and B.1.1.529 (Omicron), as well as MERS-CoV, SARS-CoV, HCoV-OC43, HCoV-229E, and HCoV-NL63. It could also inhibit infection of a pseudotyped SARS-related coronavirus WIV1 (SARSr-CoV-WIV1) from bats. Intranasal application of S-20-1 to mice before or after challenge with HCoV-OC43 or SARS-CoV-2 provided significant protection from infection. Importantly, S-20-1 was highly resistant to proteolytic degradation, had long half-life, and possessed favorable oral bioavailability. Mechanistic studies suggest that S-20-1 binds with high affinity to RBD in S1 and HR1 domain in S2 of SARS-CoV-2 S protein. Thus, with its pan-CoV fusion and entry inhibitory activity by targeting two sites in S protein, desirable half-life, and promising oral bioavailability, S-20-1 is a potential candidate for further development as a novel therapeutic and prophylactic drug against infection by SARS-CoV-2 and its variants, as well as future emerging and reemerging CoVs.

Abstract

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