Details

Autor(en) / Beteiligte

• Papini, Christina
• Ullah, Irfan
• Ranjan, Amalendu P
• Zhang, Shuo
• Wu, Qihao
• Spasov, Krasimir A
• Zhang, Chunhui
• Mothes, Walther
• Crawford, Jason M
• Lindenbach, Brett D
• Uchil, Pradeep D
• Kumar, Priti
• Jorgensen, William L
• Anderson, Karen S

Titel

Proof-of-concept studies with a computationally designed M pro inhibitor as a synergistic combination regimen alternative to Paxlovid

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2024-04, Vol.121 (17), p.e2320713121

Ort / Verlag

United States

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (M ) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug. Serious drug-drug interactions can occur with Paxlovid for patients who are also taking other medications metabolized by CYP4503A4, particularly transplant or otherwise immunocompromised patients who are most at risk for SARS-CoV-2 infection and the development of severe symptoms. Developing an alternative antiviral with improved pharmacological properties is critical for treatment of these patients. By using a computational and structure-guided approach, we were able to optimize a 100 to 250 μM screening hit to a potent nanomolar inhibitor and lead compound, Mpro61. In this study, we further evaluate Mpro61 as a lead compound, starting with examination of its mode of binding to SARS-CoV-2 M . In vitro pharmacological profiling established a lack of off-target effects, particularly CYP450 3A4 inhibition, as well as potential for synergy with the currently approved alternate antiviral, molnupiravir. Development and subsequent testing of a capsule formulation for oral dosing of Mpro61 in B6-K18-hACE2 mice demonstrated favorable pharmacological properties, efficacy, and synergy with molnupiravir, and complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate.