Design of a bifunctional pan-sarbecovirus entry inhibitor targeting the cell receptor and viral fusion protein

Jin，Hongliang1; Cheng，Lin2; Gong，Yani1; Zhu，Yuanmei1; Chong，Huihui1; Zhang，Zheng2; He，Yuxian1

2023-08-31

10.1128/jvi.00192-23

Journal of virology   Impact Factor & Quartile

0022-538X

1098-5514

Development of highly effective antivirals that are robust to viral evolution is a practical strategy for combating the continuously evolved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Inspired by viral multistep entry process, we here focus on developing a bispecific SARS-CoV-2 entry inhibitor, which acts on the cell receptor angiotensin converting enzyme 2 (ACE2) and viral S2 fusion protein. First, we identified a panel of diverse spike (S) receptor-binding domains (RBDs) and found that the RBD derived from Guangdong pangolin coronavirus (PCoV-GD) possessed the most potent antiviral potency. Next, we created a bispecific inhibitor termed RBD-IPB01 by genetically linking a peptide fusion inhibitor IPB01 to the C-terminal of PCoV-GD RBD, which exhibited greatly increased antiviral potency via cell membrane ACE2 anchoring. Promisingly, RBD-IPB01 had a uniformly bifunctional inhibition on divergent pseudo- and authentic SARS-CoV-2 variants, including multiple Omicron subvariants. RBD-IPB01 also showed consistently cross-inhibition of other sarbecoviruses, including SARS-CoV, PCoV-GD, and Guangxi pangolin coronavirus (PCoV-GX). RBD-IPB01 displayed low cytotoxicity, high trypsin resistance, and favorable metabolic stability. Combined, our studies have provided a tantalizing insight into the design of broad-spectrum and potent antiviral agent. IMPORTANCE Ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution and spillover potential of a wide variety of sarbecovirus lineages indicate the importance of developing highly effective antivirals with broad capability. By directing host angiotensin converting enzyme 2 receptor and viral S2 fusion protein, we have created a dual-targeted virus entry inhibitor with high antiviral potency and breadth. The inhibitor receptor-binding domain (RBD)-IPB01 with the Guangdong pangolin coronavirus (PCoV-GD) spike RBD and a fusion inhibitor IPB01 displays bifunctional cross-inhibitions on pseudo- and authentic SARS-CoV-2 variants including Omicron, as well as on the sarbecoviruses SARS-CoV, PCoV-GD, and Guangxi pangolin coronavirus. RBD-IPB01 also efficiently inhibits diverse SARS-CoV-2 infection of human Calu-3 cells and blocks viral S-mediated cell-cell fusion with a dual function. Thus, the creation of such a bifunctional inhibitor with pan-sarbecovirus neutralizing capability has not only provided a potential weapon to combat future SARS-CoV-2 variants or yet-to-emerge zoonotic sarbecovirus, but also verified a viable strategy for the designing of antivirals against infection of other enveloped viruses.

bifunctional entry inhibitor fusion inhibitor receptor-binding domain (RBD) sarbecoviruses SARS-CoV-2

SCI

English

Others

China Postdoctoral Science Foundation[2021M690458];

Virology

Virology

WOS:001063725700009

AMER SOC MICROBIOLOGY

MICROBIOLOGY

2-s2.0-85169297844

Scopus

1.NHC Key Laboratory of Systems Biology of Pathogens,Institute of Pathogen Biology,Chinese Academy of Medical Sciences and Peking Union Medical College,China
2.Institute of Hepatology,National Clinical Research Center for Infectious Disease,Shenzhen Third People's Hospital,Second Affiliated Hospital,School of Medicine,Southern University of Science and Technology,Shenzhen,China

Jin，Hongliang,Cheng，Lin,Gong，Yani,et al. Design of a bifunctional pan-sarbecovirus entry inhibitor targeting the cell receptor and viral fusion protein[J]. Journal of virology,2023,97(8).

Jin，Hongliang.,Cheng，Lin.,Gong，Yani.,Zhu，Yuanmei.,Chong，Huihui.,...&He，Yuxian.(2023).Design of a bifunctional pan-sarbecovirus entry inhibitor targeting the cell receptor and viral fusion protein.Journal of virology,97(8).

Jin，Hongliang,et al."Design of a bifunctional pan-sarbecovirus entry inhibitor targeting the cell receptor and viral fusion protein".Journal of virology 97.8(2023).