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Discovery of Highly Potent Fusion Inhibitors with Potential Pan-Coronavirus Activity That Effectively Inhibit Major COVID-19 Variants of Concern (VOCs) in Pseudovirus-Based Assays

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Laboratory of Molecular Modeling & Drug Design, New York Blood Center, Lindsley F. Kimball Research Institute, New York, NY 10065, USA
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Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555, USA
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Department of Chemistry & Physics, Augusta University, Augusta, GA 30912, USA
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EDASA Scientific, Scientific Campus, Moscow State University, Leninskie Gory Bld. 75, 77-101b, 119992 Moscow, Russia
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Center of Biodefense and Emerging Disease, The University of Texas Medical Branch, Galveston, TX 77555, USA
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New York Blood Center, New York, NY 10065, USA
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Authors to whom correspondence should be addressed.
Academic Editor: Ester Ballana Guix
Viruses 2022, 14(1), 69; https://doi.org/10.3390/v14010069
Received: 22 November 2021 / Revised: 26 December 2021 / Accepted: 29 December 2021 / Published: 31 December 2021
(This article belongs to the Special Issue COVID-19—Advances in Clinical and Epidemiological Aspects)
We report the discovery of several highly potent small molecules with low-nM potency against severe acute respiratory syndrome coronavirus (SARS-CoV; lowest half-maximal inhibitory concentration (IC50: 13 nM), SARS-CoV-2 (IC50: 23 nM), and Middle East respiratory syndrome coronavirus (MERS-CoV; IC50: 76 nM) in pseudovirus-based assays with excellent selectivity index (SI) values (>5000), demonstrating potential pan-coronavirus inhibitory activities. Some compounds showed 100% inhibition against the cytopathic effects (CPE; IC100) of an authentic SARS-CoV-2 (US_WA-1/2020) variant at 1.25 µM. The most active inhibitors also potently inhibited variants of concern (VOCs), including the UK (B.1.1.7) and South African (B.1.351) variants and the Delta variant (B.1.617.2) originally identified in India in pseudovirus-based assay. Surface plasmon resonance (SPR) analysis with one potent inhibitor confirmed that it binds to the prefusion SARS-CoV-2 spike protein trimer. These small-molecule inhibitors prevented virus-mediated cell–cell fusion. The absorption, distribution, metabolism, and excretion (ADME) data for one of the most active inhibitors, NBCoV1, demonstrated drug-like properties. An in vivo pharmacokinetics (PK) study of NBCoV1 in rats demonstrated an excellent half-life (t1/2) of 11.3 h, a mean resident time (MRT) of 14.2 h, and oral bioavailability. We expect these lead inhibitors to facilitate the further development of preclinical and clinical candidates. View Full-Text
Keywords: severe acute respiratory syndrome (SARS); SARS-CoV; SARS-CoV-2; middle east respiratory syndrome (MERS); MERS-CoV; COVID-19; pan-coronavirus; fusion inhibitor severe acute respiratory syndrome (SARS); SARS-CoV; SARS-CoV-2; middle east respiratory syndrome (MERS); MERS-CoV; COVID-19; pan-coronavirus; fusion inhibitor
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MDPI and ACS Style

Curreli, F.; Ahmed, S.; Victor, S.M.B.; Drelich, A.; Panda, S.S.; Altieri, A.; Kurkin, A.V.; Tseng, C.-T.K.; Hillyer, C.D.; Debnath, A.K. Discovery of Highly Potent Fusion Inhibitors with Potential Pan-Coronavirus Activity That Effectively Inhibit Major COVID-19 Variants of Concern (VOCs) in Pseudovirus-Based Assays. Viruses 2022, 14, 69. https://doi.org/10.3390/v14010069

AMA Style

Curreli F, Ahmed S, Victor SMB, Drelich A, Panda SS, Altieri A, Kurkin AV, Tseng C-TK, Hillyer CD, Debnath AK. Discovery of Highly Potent Fusion Inhibitors with Potential Pan-Coronavirus Activity That Effectively Inhibit Major COVID-19 Variants of Concern (VOCs) in Pseudovirus-Based Assays. Viruses. 2022; 14(1):69. https://doi.org/10.3390/v14010069

Chicago/Turabian Style

Curreli, Francesca, Shahad Ahmed, Sofia M.B. Victor, Aleksandra Drelich, Siva S. Panda, Andrea Altieri, Alexander V. Kurkin, Chien-Te K. Tseng, Christopher D. Hillyer, and Asim K. Debnath. 2022. "Discovery of Highly Potent Fusion Inhibitors with Potential Pan-Coronavirus Activity That Effectively Inhibit Major COVID-19 Variants of Concern (VOCs) in Pseudovirus-Based Assays" Viruses 14, no. 1: 69. https://doi.org/10.3390/v14010069

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