We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
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.
- Authors
Curreli, Francesca; Ahmed, Shahad; Victor, Sofia M. B.; Drelich, Aleksandra; Panda, Siva S.; Altieri, Andrea; Kurkin, Alexander V.; Tseng, Chien-Te K.; Hillyer, Christopher D.; Debnath, Asim K.
- 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.
- Subjects
MIDDLE East; COVID-19; CORONAVIRUSES; MIDDLE East respiratory syndrome; MERS coronavirus; SARS disease; SARS-CoV-2; SURFACE plasmon resonance; CELL fusion
- Publication
Viruses (1999-4915), 2022, Vol 14, Issue 1, p69
- ISSN
1999-4915
- Publication type
Article
- DOI
10.3390/v14010069