tetano
Editor, Senior Moderator
Antimicrob Agents Chemother
. 2024 Sep 3:e0056224.
doi: 10.1128/aac.00562-24. Online ahead of print. Design of novel and highly selective SARS-CoV-2 main protease inhibitors
Adi N R Poli[SUP] 1 [/SUP], Ian Tietjen[SUP] 2 [/SUP], Nitesh K Nandwana[SUP] 1 [/SUP], Joel Cassel[SUP] 3 [/SUP], Troy E Messick[SUP] 4 [/SUP], Emery T Register[SUP] 2 [/SUP], Frederick Keeney[SUP] 2 [/SUP], Rajesh Rajaiah[SUP] 5 [/SUP], Atul K Verma[SUP] 5 [/SUP], Kabita Pandey[SUP] 5 [/SUP], Arpan Acharya[SUP] 5 [/SUP], Siddappa N Byrareddy[SUP] 5 [/SUP], Luis J Montaner[SUP] 2 [/SUP], Joseph M Salvino[SUP] 1 3 6 [/SUP]
Affiliations
We have synthesized a novel and highly selective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease peptide mimetic inhibitor mimicking the replicase 1ab recognition sequence -Val-Leu-Gln- and utilizing a cysteine selective acyloxymethyl ketone as the electrophilic warhead to target the active site Cys145. Utilizing a constrained cyclic peptide that locks the conformation between the P3 (Val) and P2 (Leu) residues, we identified a highly selective inhibitor that fills the P2 pocket occupied by the leucine residue sidechain of PF-00835231 and the dimethyl-3-azabicyclo-hexane motif in nirmatrelvir (PF-07321332). This strategy resulted in potent and highly selective Mpro inhibitors without inhibiting essential host cathepsin cysteine or serine proteases. The lead prototype compound 1 (MPro IC[SUB]50[/SUB] = 230 ± 18 nM) also inhibits the replication of multiple SARS-CoV-2 variants in vitro, including SARS-CoV-2 variants of concern, and can synergize at lower concentrations with the viral RNA polymerase inhibitor, remdesivir, to inhibit replication. It also reduces SARS-CoV-2 replication in SARS-CoV-2 Omicron-infected Syrian golden hamsters without obvious toxicities, demonstrating in vivo efficacy. This novel lead structure provides the basis for optimization of improved agents targeting evolving SARS-CoV-2 drug resistance that can selectively act on Mpro versus host proteases and are less likely to have off-target effects due to non-specific targeting. Developing inhibitors against the active site of the main protease (Mpro), which is highly conserved across coronaviruses, is expected to impart a higher genetic barrier to evolving SARS-CoV-2 drug resistance. Drugs that selectively inhibit the viral Mpro are less likely to have off-target effects warranting efforts to improve this therapy.
Keywords: SARS-CoV-2; benzoxazepine; peptide mimetic; protease inhibitor.
. 2024 Sep 3:e0056224.
doi: 10.1128/aac.00562-24. Online ahead of print. Design of novel and highly selective SARS-CoV-2 main protease inhibitors
Adi N R Poli[SUP] 1 [/SUP], Ian Tietjen[SUP] 2 [/SUP], Nitesh K Nandwana[SUP] 1 [/SUP], Joel Cassel[SUP] 3 [/SUP], Troy E Messick[SUP] 4 [/SUP], Emery T Register[SUP] 2 [/SUP], Frederick Keeney[SUP] 2 [/SUP], Rajesh Rajaiah[SUP] 5 [/SUP], Atul K Verma[SUP] 5 [/SUP], Kabita Pandey[SUP] 5 [/SUP], Arpan Acharya[SUP] 5 [/SUP], Siddappa N Byrareddy[SUP] 5 [/SUP], Luis J Montaner[SUP] 2 [/SUP], Joseph M Salvino[SUP] 1 3 6 [/SUP]
Affiliations
- PMID: 39225484
- DOI: 10.1128/aac.00562-24
We have synthesized a novel and highly selective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease peptide mimetic inhibitor mimicking the replicase 1ab recognition sequence -Val-Leu-Gln- and utilizing a cysteine selective acyloxymethyl ketone as the electrophilic warhead to target the active site Cys145. Utilizing a constrained cyclic peptide that locks the conformation between the P3 (Val) and P2 (Leu) residues, we identified a highly selective inhibitor that fills the P2 pocket occupied by the leucine residue sidechain of PF-00835231 and the dimethyl-3-azabicyclo-hexane motif in nirmatrelvir (PF-07321332). This strategy resulted in potent and highly selective Mpro inhibitors without inhibiting essential host cathepsin cysteine or serine proteases. The lead prototype compound 1 (MPro IC[SUB]50[/SUB] = 230 ± 18 nM) also inhibits the replication of multiple SARS-CoV-2 variants in vitro, including SARS-CoV-2 variants of concern, and can synergize at lower concentrations with the viral RNA polymerase inhibitor, remdesivir, to inhibit replication. It also reduces SARS-CoV-2 replication in SARS-CoV-2 Omicron-infected Syrian golden hamsters without obvious toxicities, demonstrating in vivo efficacy. This novel lead structure provides the basis for optimization of improved agents targeting evolving SARS-CoV-2 drug resistance that can selectively act on Mpro versus host proteases and are less likely to have off-target effects due to non-specific targeting. Developing inhibitors against the active site of the main protease (Mpro), which is highly conserved across coronaviruses, is expected to impart a higher genetic barrier to evolving SARS-CoV-2 drug resistance. Drugs that selectively inhibit the viral Mpro are less likely to have off-target effects warranting efforts to improve this therapy.
Keywords: SARS-CoV-2; benzoxazepine; peptide mimetic; protease inhibitor.