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

Francesca Curreli, Shahad Ahmed, Sofia M.B. Victor, Aleksandra Drelich, Siva S. Panda, Andrea Altieri, Alexander V. Kurkin, Chien Te K. Tseng, Christopher D. Hillyer, Asim K. Debnath

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number69
JournalViruses
Volume14
Issue number1
DOIs
StatePublished - Jan 2022

Keywords

  • COVID-19
  • Fusion inhibitor
  • MERS-CoV
  • Middle east respiratory syndrome (MERS)
  • Pan-coronavirus
  • SARS-CoV
  • SARS-CoV-2
  • Severe acute respiratory syndrome (SARS)

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology

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