Dynamic Combinatorial Chemistry Unveils Nsp10 Inhibitors with Antiviral Potential Against SARS-CoV-2

Area of Science:

• Virology
• Drug Discovery
• Biochemistry

Background:

• Limited treatment options exist for SARS-CoV-2, the virus causing COVID-19.
• The viral 3'-5' exoribonuclease (ExoN) and 2'-O-methyltransferase (2'-O-MTase) are crucial for viral viability.
• These enzymes, Nsp14 and Nsp16, function with cofactor Nsp10, representing underexplored drug targets.

Purpose of the Study:

• To identify small molecules that inhibit the enzymatic activities of SARS-CoV-2 Nsp14 and Nsp16.
• To disrupt the protein-protein interactions (PPI) involving Nsp10 with Nsp14 and Nsp16.
• To evaluate the antiviral potential of identified inhibitors against coronaviruses.

Main Methods:

• Utilized target-directed dynamic combinatorial chemistry (tdDCC) to discover Nsp10 binders.
• Synthesized identified compounds and assessed their affinity for Nsp10.
• Evaluated inhibition of ExoN and 2'-O-MTase activities and antiviral effects in cell-based assays.

Main Results:

• A novel class of inhibitors targeting ExoN and/or 2'-O-MTase was identified.
• These inhibitors demonstrated binding to Nsp10 and modulated the activity of its complexes.
• The identified compounds exhibited significant antiviral activity against human coronavirus 229E (hCoV-229E) and SARS-CoV-2.

Conclusions:

• Nsp10-interacting compounds represent a promising new avenue for antiviral drug development.
• The identified inhibitors offer potential therapeutic agents against current and future coronavirus outbreaks.
• This study validates ExoN and 2'-O-MTase as viable targets for broad-spectrum coronavirus therapeutics.