tetano
Editor, Senior Moderator
Nat Commun
. 2025 Feb 13;16(1):1604.
doi: 10.1038/s41467-025-56902-x. Design of quinoline SARS-CoV-2 papain-like protease inhibitors as oral antiviral drug candidates
Prakash Jadhav[SUP] #[/SUP][SUP] 1 [/SUP], Xueying Liang[SUP] #[/SUP][SUP] 2 [/SUP], Ahmadullah Ansari[SUP] #[/SUP][SUP] 3 4 [/SUP], Bin Tan[SUP] #[/SUP][SUP] 1 [/SUP], Haozhou Tan[SUP] 1 [/SUP], Kan Li[SUP] 1 [/SUP], Xiang Chi[SUP] 2 [/SUP], Alexandra Ford[SUP] 5 [/SUP], Francesc Xavier Ruiz[SUP] 6 7 [/SUP], Eddy Arnold[SUP] 8 9 [/SUP], Xufang Deng[SUP] 10 11 [/SUP], Jun Wang[SUP] 12 [/SUP]
Affiliations
The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents the systematic design of quinoline-containing SARS-CoV-2 papain-like protease (PL[SUP]pro[/SUP]) inhibitors as potential oral antiviral drug candidates. By leveraging the recently discovered Val70[SUP]Ub[/SUP] binding site in PL[SUP]pro[/SUP], we designed a series of quinoline analogs demonstrating potent PL[SUP]pro[/SUP] inhibition and antiviral activity. Notably, the X-ray crystal structures of 6 lead compounds reveal that the 2-aryl substitution can occupy either the Val70[SUP]Ub[/SUP] site as expected or the BL2 groove in a flipped orientation. The in vivo lead Jun13296 exhibits favorable pharmacokinetic properties and potent inhibition against SARS-CoV-2 variants and nirmatrelvir-resistant mutants. In a mouse model of SARS-CoV-2 infection, oral treatment with Jun13296 significantly improves survival, reduces body weight loss and lung viral titers, and prevents lung tissue damage. These results underscore the potential of quinoline PL[SUP]pro[/SUP] inhibitors as promising oral SARS-CoV-2 antiviral candidates, instilling hope for the future of SARS-CoV-2 treatment.
. 2025 Feb 13;16(1):1604.
doi: 10.1038/s41467-025-56902-x. Design of quinoline SARS-CoV-2 papain-like protease inhibitors as oral antiviral drug candidates
Prakash Jadhav[SUP] #[/SUP][SUP] 1 [/SUP], Xueying Liang[SUP] #[/SUP][SUP] 2 [/SUP], Ahmadullah Ansari[SUP] #[/SUP][SUP] 3 4 [/SUP], Bin Tan[SUP] #[/SUP][SUP] 1 [/SUP], Haozhou Tan[SUP] 1 [/SUP], Kan Li[SUP] 1 [/SUP], Xiang Chi[SUP] 2 [/SUP], Alexandra Ford[SUP] 5 [/SUP], Francesc Xavier Ruiz[SUP] 6 7 [/SUP], Eddy Arnold[SUP] 8 9 [/SUP], Xufang Deng[SUP] 10 11 [/SUP], Jun Wang[SUP] 12 [/SUP]
Affiliations
- PMID: 39948104
- DOI: 10.1038/s41467-025-56902-x
The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents the systematic design of quinoline-containing SARS-CoV-2 papain-like protease (PL[SUP]pro[/SUP]) inhibitors as potential oral antiviral drug candidates. By leveraging the recently discovered Val70[SUP]Ub[/SUP] binding site in PL[SUP]pro[/SUP], we designed a series of quinoline analogs demonstrating potent PL[SUP]pro[/SUP] inhibition and antiviral activity. Notably, the X-ray crystal structures of 6 lead compounds reveal that the 2-aryl substitution can occupy either the Val70[SUP]Ub[/SUP] site as expected or the BL2 groove in a flipped orientation. The in vivo lead Jun13296 exhibits favorable pharmacokinetic properties and potent inhibition against SARS-CoV-2 variants and nirmatrelvir-resistant mutants. In a mouse model of SARS-CoV-2 infection, oral treatment with Jun13296 significantly improves survival, reduces body weight loss and lung viral titers, and prevents lung tissue damage. These results underscore the potential of quinoline PL[SUP]pro[/SUP] inhibitors as promising oral SARS-CoV-2 antiviral candidates, instilling hope for the future of SARS-CoV-2 treatment.