8UR9

Crystal Structure of the SARS-CoV-2 Main Protease in Complex with Compound 61

Summary for 8UR9

• Entry DOI: 10.2210/pdb8ur9/pdb
• Descriptor: 3C-like proteinase nsp5, (5P)-5-[(1P,3M,3'P)-3-{3-chloro-5-[(2-chlorophenyl)methoxy]-4-fluorophenyl}-2-oxo-2H-[1,3'-bipyridin]-5-yl]-1-methylpyrimidine-2,4(1H,3H)-dione (3 entities in total)
• Functional Keywords: hydrolase, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 68216.47

Authors

Papini, C.,Zhang, C.H.,Jorgensen, W.L.,Anderson, K.S. (deposition date: 2023-10-25, release date: 2024-05-15)

Primary citation

Papini, C.,Ullah, I.,Ranjan, A.P.,Zhang, S.,Wu, Q.,Spasov, K.A.,Zhang, C.,Mothes, W.,Crawford, J.M.,Lindenbach, B.D.,Uchil, P.D.,Kumar, P.,Jorgensen, W.L.,Anderson, K.S.
Proof-of-concept studies with a computationally designed M pro inhibitor as a synergistic combination regimen alternative to Paxlovid.
Proc.Natl.Acad.Sci.USA, 121:e2320713121-e2320713121, 2024

PubMed Abstract: 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.

PubMed: 38621119
DOI: 10.1073/pnas.2320713121

Experimental method

X-RAY DIFFRACTION (2.3 Å)