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

doi:10.3390/v14010069

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.

Highlights

Licensee MDPI, Basel, Switzerland.The outbreak of coronavirus disease 2019 (COVID-19), caused by the novel coronavirus (CoV) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and first reported in December 2019 in Wuhan [1], China, has led to massive human suffering, death, and economic devastation worldwide
SARS-CoV-2 is a positive-sense, enveloped, single-stranded RNA virus that belongs to the family Coronaviridae, along with two other CoVs that have been responsible for major outbreaks in recent years: SARS-CoV, which originated in China in 2003, and the Middle East respiratory syndrome CoV (MERS-CoV), which originated in Saudi Arabia in 2012
We found that NBCoV5 only inhibited SARS-CoV-2–mediated cell-to-cell fusion at higher doses (68% inhibition at 4 μM; Figure 4), whereas NBCoV1, NBCoV2, and NBCoV4 potently inhibited cell-to-cell fusion, even at the lowest dose used in this assay (250 nM), which was associated with 62–79%

Summary

Introduction

The outbreak of coronavirus disease 2019 (COVID-19), caused by the novel coronavirus (CoV) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and first reported in December 2019 in Wuhan [1], China, has led to massive human suffering, death, and economic devastation worldwide. Other COVID-19 vaccines recommended by WHO and several other countries are Covishield by Oxford/Astra-Zeneca, UK, CoronaVac from Sinovac, China, Covaxin by Bharat Biotec, India. Despite these breakthroughs in vaccine development, effective vaccines may not reach all individuals on a global scale. The development of novel drugs able to treat or prevent SARS-CoV-2 infection remains urgently necessary. Prior outbreaks were severe, they have been eclipsed by the current

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