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

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.
Songyi Xue # 1,  Xinling Wang # 2,  Lei Wang 1,  Wei Xu 2,  Shuai Xia 2,  Lujia Sun 2,  Shaohui Wang 3,  Ning Shen 1,  Ziqi Yang 1,  Bo Huang 1,  Sihao Li 1,  Chuanhai Cao 1 4,  Laurent Calcul 1,  Xingmin Sun 3,  Lu Lu 5,  Jianfeng Cai 6,  Shibo Jiang 7
Affiliations

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.
PMID: 36075899 DOI: 10.1038/s41421-022-00455-6
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.

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