Discovery of Novel Isofunctional SARS-CoV‑2 NSP14 RNA Cap Methyltransferase Inhibitors by Structure-Based Virtual...

Area of Science:

• Virology
• Drug Discovery
• Computational Chemistry

Background:

• The COVID-19 pandemic caused millions of deaths globally.
• Direct-acting antivirals (DAAs) are crucial for managing severe COVID-19 in at-risk individuals.
• Targeting viral enzymes like SARS-CoV-2's NSP14 is a key strategy for antiviral development.

Purpose of the Study:

• To identify novel SAH-dependent inhibitors of the SARS-CoV-2 RNA cap methyltransferase NSP14.
• To explore the utility of structure-based virtual screening (SBVS) for discovering new antiviral compounds.
• To find chemically distinct NSP14 inhibitors as potential starting points for new DAAs.

Main Methods:

• Employed a structure-based virtual screening (SBVS) workflow.
• Screened large compound libraries, including Enamine REAL make-on-demand.
• Conducted biochemical testing and determined half-maximal inhibitory concentrations (IC50).

Main Results:

• Virtual screening of the Enamine REAL library yielded higher hit rates and better docking scores.
• Biochemical testing identified 10 novel NSP14 inhibitors from synthesized Enamine REAL compounds.
• These inhibitors showed half-maximal inhibitory concentrations (IC50) below 10 μM and were chemically distinct from previously known inhibitors.

Conclusions:

• Structure-based virtual screening is effective for discovering novel antiviral compounds against SARS-CoV-2.
• The identified NSP14 inhibitors represent promising leads for developing new direct-acting antivirals (DAAs).
• These novel compounds could advance the development of therapeutics to combat SARS-CoV-2.