Discovery of Highly Potent Small Molecule Pan-Coronavirus Fusion Inhibitors

• Published in: Viruses Vol. 15; no. 4; p. 1001
• Main Authors: Curreli, Francesca, Chau, Kent, Tran, Thanh-Thuy, Nicolau, Isabella, Ahmed, Shahad, Das, Pujita, Hillyer, Christopher D, Premenko-Lanier, Mary, Debnath, Asim K
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-04-2023; MDPI
• Subjects: Anti-Retroviral Agents; Antibodies; Antiviral agents; authentic viruses; Cell fusion; Chemical inhibitors; Control; Coronaviruses; COVID-19; COVID-19 vaccines; Cytotoxicity; Drug development; Drugs; Health aspects; HIV; Human immunodeficiency virus; Humans; MERS-CoV; Middle East respiratory syndrome; Middle East Respiratory Syndrome Coronavirus; Mutation; Pandemics; Proteins; pseudoviruses; SARS-CoV; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Variants of Concern (VoC); Viruses; United States; New York; United States > US; SARS-CoV-2; authentic viruses; Variants of Concern (VoC); ADME; SARS-CoV; MERS-CoV; pseudoviruses
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v15041001

The unprecedented pandemic of COVID-19, caused by a novel coronavirus, SARS-CoV-2, and its highly transmissible variants, led to massive human suffering, death, and economic devastation worldwide. Recently, antibody-evasive SARS-CoV-2 subvariants, BQ and XBB, have been reported. Therefore, the continued development of novel drugs with pan-coronavirus inhibition is critical to treat and prevent infection of COVID-19 and any new pandemics that may emerge. We report the discovery of several highly potent small-molecule inhibitors. One of which, NBCoV63, showed low nM potency against SARS-CoV-2 (IC
: 55 nM), SARS-CoV-1 (IC
: 59 nM), and MERS-CoV (IC
: 75 nM) in pseudovirus-based assays with excellent selectivity indices (SI > 900), suggesting its pan-coronavirus inhibition. NBCoV63 showed equally effective antiviral potency against SARS-CoV-2 mutant (D614G) and several variants of concerns (VOCs) such as B.1.617.2 (Delta), B.1.1.529/BA.1 and BA.4/BA.5 (Omicron), and K417T/E484K/N501Y (Gamma). NBCoV63 also showed similar efficacy profiles to Remdesivir against authentic SARS-CoV-2 (Hong Kong strain) and two of its variants (Delta and Omicron), SARS-CoV-1, and MERS-CoV by plaque reduction in Calu-3 cells. Additionally, we show that NBCoV63 inhibits virus-mediated cell-to-cell fusion in a dose-dependent manner. Furthermore, the absorption, distribution, metabolism, and excretion (ADME) data of NBCoV63 demonstrated drug-like properties.