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FINDING LIGANDS TARGETING THE CONSERVED RNA BINDING SITE OF SARS-CoV-2 NSP13
The second CACHE Challenge target is the NSP13 helicase of SARS-CoV-2.
Participants are asked to find hits for the RNA-binding site of NSP13. Read more under Details below.
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RNA binding site of SARS-CoV-2 NSP13
|Disease association||Alpha- and beta-coronaviruses including SARS-CoV-2|
Finding ligands targeting the conserved RNA binding site of SARS-CoV-2 NSP13.
Predicted compounds will be procured and tested at CACHE using both enzymatic and binding assays.
Helicase inhibition is not a novel anti-viral strategy and potent inhibitors of herpes simplex virus, shingles and hepatitis C viruses have been reported. Helicase inhibitor Pritelivir is in Phase III clinical trials and Amenamevir has been approved in Japan for shingles. In contrast, the SARS-CoV-2 helicase NSP13 has so far been underexplored. The RNA-binding site of NSP13 is the most conserved site in SARS-CoV-2 and across coronaviruses, and the underlying selective pressure is expected to apply to future coronavirus outbreaks: drugs binding this site should be effective against future pandemic threats.
RNA unwinding is mechanistically coupled to hydrolysis of a nucleotide triphosphate (generally ATP) at a pocket distinct from the RNA binding site and existing helicase inhibitors either bind the ATP site to prevent ATP hydrolysis, or bind the nucleic acid substrate to antagonize the unwinding activity. The ATP site of NSP13 is significantly less conserved across coronaviruses than the RNA binding pocket .
The crystal structure of NSP13 has been determined in multiple states and crystal forms. In particular, fragments found in PDB IDs 5RLH, 5RLZ, 5RML, 5RMM overlap with the evolutionary conserved RNA-binding site and may guide the design of more potent molecules.
There are no drug candidates targeting the SARS-CoV-2 helicase.
The public release of chemical starting points that compete with RNA binding will facilitate the rapid development of selective, potent, cell-active inhibitors. The intended long-term impact is to accelerate the discovery of a coronavirus antiviral that is complementary to existing therapies such as Paxlovid (target: Mpro) and Molnupiravir (target: RdRp) and that would also be effective against future coronavirus outbreaks.