The NSP14/NSP10 RNA repair complex as a Pan-coronavirus therapeutic target

Abstract

The risk of zoonotic coronavirus spillover into the human population, as highlighted by the SARS-CoV-2 pandemic, demands the development of pan-coronavirus antivirals. The efficacy of existing antiviral ribonucleoside/ribonucleotide analogs, such as remdesivir, is decreased by the viral proofreading exonuclease NSP14-NSP10 complex. Here, using a novel assay and in silico modeling and screening, we identified NSP14-NSP10 inhibitors that increase remdesivir’s potency. A model compound, sofalcone, both inhibits the exonuclease activity of SARS-CoV-2, SARS-CoV, and MERS-CoV in vitro, and synergistically enhances the antiviral effect of remdesivir, suppressing the replication of SARS-CoV-2 and the related human coronavirus OC43. The validation of top hits from our primary screenings using cellular systems provides proof-of-concept for the NSP14 complex as a therapeutic target.

SARS-CoV-2 virus NSP14 Impairs NRF2/HMOX1 activation by targeting Sirtuin 1

“…The exonuclease activity of NSP14 is stimulated by the cofactor nsp10, whereas the N7-MTase activity of NSP14 does not depend on the cofactor NSP10 [ 21 – 23 ]. The ExoN and N7-MTase enzymatic activities of NSP14 are critical for inducing RNA modifications that are essential for viral RNA stability and translation as well as for preventing the activation of the host immune response, making it an attractive target for the development of new COVID-19 antiviral therapeutics [ 24 – 26 ].…”

A Helquat-like Compound as a Potent Inhibitor of Flaviviral and Coronaviral Polymerases

“…Two compounds targeting the RdRp (remdesivir and molnupiravir) and the 3C-like protease inhibitor nirmatrelvir (sold under the name Paxlovid) are already available as human medicines. In addition, inhibitors of other coronaviral enzymes, such as the helicase [ 27 , 28 ], endo- and exonuclease [ 29 , 30 ] or the methyltransferases [ 18 , 19 , 31 ], have been actively developed. However, the goal is to develop compounds that would be active against multiple viruses or even multiple viral families.…”

Recent insights into the structure and function of coronavirus ribonucleases

“…Recent research efforts have also led to the design of medium‐ and high‐throughput inhibitor assays for studying the inhibition of Nsp14 ExoN [ 80 , 81 ]. These assays (FRET‐based) provide a quick throughput and have already shown promise to identify predicted active site inhibitors with low micromolar (µ m ) IC 50 and decreased EC 50 in combination with remdesivir.…”