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Discovery of Highly Potent Small Molecule Pan-Coronavirus Fusion Inhibitors
Francesca Curreli1, Kent Chau2, Thanh-Thuy Tran2
1Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
Abstract:
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 (IC50: 55 nM), SARS-CoV-1 (IC50: 59 nM), and MERS-CoV (IC50: 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.
Insights
A new small molecule, NBCoV63, shows potent pan-coronavirus inhibition against SARS-CoV-2, SARS-CoV-1, and MERS-CoV. This drug candidate demonstrates broad efficacy against variants and favorable drug-like properties for potential therapeutic use.
Area of Science:
- Virology
- Drug Discovery
- Medicinal Chemistry
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, has resulted in global health and economic crises.
- Emerging antibody-evasive variants like BQ and XBB necessitate the development of broad-spectrum antiviral agents.
- Pan-coronavirus inhibitors are crucial for managing current and future viral pandemic threats.
Purpose of the Study:
- To discover and characterize novel small-molecule inhibitors with pan-coronavirus activity.
- To evaluate the antiviral potency and selectivity of identified inhibitors against various coronaviruses and their variants.
- To assess the drug-like properties of promising inhibitor candidates.
Main Methods:
- Pseudovirus-based assays were employed to determine the inhibitory concentrations (IC50) against SARS-CoV-2, SARS-CoV-1, and MERS-CoV.
- Antiviral potency was tested against SARS-CoV-2 mutants and variants of concern (VOCs) including Delta and Omicron.
- Plaque reduction assays in Calu-3 cells were used to compare efficacy with Remdesivir against authentic viruses and variants.
- Inhibition of virus-mediated cell-to-cell fusion and ADME profiling were conducted.
Main Results:
- NBCoV63 demonstrated low nanomolar potency against SARS-CoV-2 (IC50: 55 nM), SARS-CoV-1 (IC50: 59 nM), and MERS-CoV (IC50: 75 nM) with high selectivity (SI > 900).
- NBCoV63 exhibited potent antiviral activity against SARS-CoV-2 D614G mutant, Delta, Omicron (BA.1, BA.4/BA.5), and Gamma variants.
- The compound showed comparable efficacy to Remdesivir against authentic SARS-CoV-2, SARS-CoV-1, and MERS-CoV, including variants.
- NBCoV63 effectively inhibited virus-mediated cell-to-cell fusion in a dose-dependent manner and displayed favorable ADME properties.
Conclusions:
- NBCoV63 is a potent small-molecule inhibitor with broad-spectrum activity against multiple coronaviruses, including clinically relevant variants.
- Its ability to inhibit cell-to-cell fusion and favorable pharmacokinetic profile suggest its potential as a therapeutic agent for COVID-19 and future coronavirus outbreaks.
- The discovery of NBCoV63 offers a promising avenue for developing new treatments against emerging and re-emerging coronavirus infections.
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