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

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Yale University; Yale University; Yale University; Yale University; Yale University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11631
• DOI: 10.1073/pnas.2320713121
• 发表日期: 2024-04-23
• 关键词: main protease; DRUG; sars-cov-2; reveals

摘要

As the SARSCoV - 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 SARSCoV - 2 main protease (M pro ) 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 SARSCoV - 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 mu M 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 SARSCoV - 2 M pro . In vitro pharmacological profiling established a lack of offtarget 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 SARSCoV - 2, establishing Mpro61 as a promising potential preclinical candidate.