Publications -- Amalendu Ranjan
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/31935
This collection is limited to articles published under the terms of a creative commons license or other open access publishing agreement since 2016. It is not intended as a complete list of the author's works.
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Browsing Publications -- Amalendu Ranjan by Author "Crawford, Jason M."
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Item Proof-of-concept studies with a computationally designed M(pro) inhibitor as a synergistic combination regimen alternative to Paxlovid(National Academy of Sciences, 2024-04-15) Papini, Christina; Ullah, Ifan; 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.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(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 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 muM 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(pro). 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.