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An exonuclease-resistant chain-terminating nucleotide analogue targeting the SARS-CoV-2 replicase complex

Nucleotide analogues (NA) are currently employed for treatment of several viral diseases, including COVID-19. NA prodrugs are intracellularly activated to the 5'-triphosphate form. They are incorporated into the viral RNA by the viral polymerase (SARS-CoV-2 nsp12), terminating or corrupting RNA synthesis. For Coronaviruses, natural resistance to NAs is provided by a viral 3'-to-5' exonuclease heterodimer nsp14/nsp10, which can remove terminal analogues. Here, we show that the replacement of the α-phosphate of Bemnifosbuvir 5'-triphosphate form (AT-9010) by an α-thiophosphate renders it resistant to excision. The resulting α-thiotriphosphate, AT-9052, exists as two epimers (RP/SP). Through co-crystallization and activity assays, we show that the Sp isomer is preferentially used as a substrate by nucleotide diphosphate kinase (NDPK), and by SARS-CoV-2 nsp12, where its incorporation causes immediate chain-termination. The same -Sp isomer, once incorporated by nsp12, is also totally resistant to the excision by nsp10/nsp14 complex. However, unlike AT-9010, AT-9052-RP/SP no longer inhibits the N-terminal nucleotidylation domain of nsp12. We conclude that AT-9052-Sp exhibits a unique mechanism of action against SARS-CoV-2. Moreover, the thio modification provides a general approach to rescue existing NAs whose activity is hampered by coronavirus proofreading capacity.

 

Comments:

That's an intriguing study! It seems like a sophisticated approach to modifying nucleotide analogues to combat the viral resistance mechanisms found in Coronaviruses, particularly SARS-CoV-2. The modification of Bemnifosbuvir to create the α-thiotriphosphate form, AT-9052, and its two epimers (RP/SP) demonstrates not only a resistance to excision by the nsp14/nsp10 complex but also a unique mechanism of action against SARS-CoV-2 through immediate chain termination upon incorporation by the viral polymerase, nsp12.

This innovative modification not only addresses the issue of viral exonuclease-mediated resistance but also showcases the potential to rescue existing nucleotide analogues whose effectiveness might be compromised by viral proofreading capacities. The ability of AT-9052-Sp to evade excision while maintaining efficacy against SARS-CoV-2 presents a promising advancement in antiviral drug development.

The study's findings hint at a broader implication in combating viral diseases beyond COVID-19 by offering a general approach to enhance the efficacy of nucleotide analogues affected by proofreading mechanisms present in other viruses. This approach could potentially revolutionize the development of antiviral treatments against a spectrum of viral infections.

The unique mechanism of action exhibited by AT-9052-Sp against SARS-CoV-2 suggests a promising avenue for further research and development in antiviral drug design.

Related Products

Cat.No. Product Name Information
E1013 Bemnifosbuvir Hemisulfate (AT-527)

Bemnifosbuvir Hemisulfate (AT-527, RG-6422, RO 7496998) is a hemi-sulfate salt of AT-511. AT-511 is a potent inhibitor of SARS-CoV-2 with an EC90 of 0.47 μM.

Related Targets

SARS-CoV