9GIJ

Crystal structure of SARS-CoV-2 Mpro with compound 5

This is a non-PDB format compatible entry.

Summary for 9GIJ

• Entry DOI: 10.2210/pdb9gij/pdb
• Descriptor: 3C-like proteinase nsp5, (2~{R})-3-(4-chlorophenyl)-2-[2-[(2~{R})-1-isoquinolin-4-ylcarbonylpyrrolidin-2-yl]ethanoyl-methyl-amino]-~{N}-methyl-propanamide (3 entities in total)
• Functional Keywords: mpro, sars-cov-2, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34318.54

Authors

Prasad, A.,Schmitt, A.,Preuss, F.,Maskos, K.,Wang, X.,Gotchev, D.,Konz Makino, D.L. (deposition date: 2024-08-19, release date: 2024-11-06)

Primary citation

Wang, X.,Gotchev, D.,Fan, K.Y.,Vega, M.M.,Mani, N.,McGovern-Gooch, K.,Cuconati, A.,Tercero, B.,Wang, X.,Carpino, P.,Maskos, K.,Centrella, P.A.,Schmitt, A.,Preuss, F.,Prasad, A.,Chen, C.Y.,Clark, M.A.,Guilinger, J.P.,Johnstone, S.,von Konig, K.,Keefe, A.D.,Liu, J.,Turcotte, S.,Zhang, Y.,Konz Makino, D.L.,Lam, A.M.,Cole, A.G.,Sofia, M.J.
Rational Design of Macrocyclic Noncovalent Inhibitors of SARS-CoV-2 M pro from a DNA-Encoded Chemical Library Screening Hit That Demonstrate Potent Inhibition against Pan-Coronavirus Homologues and Nirmatrelvir-Resistant Variants.
J.Med.Chem., 2024

PubMed Abstract: The recent global COVID-19 pandemic has highlighted treatments for coronavirus infection as an unmet medical need. The main protease (M) has been an important target for the development of SARS-CoV-2 direct-acting antivirals. Nirmatrelvir as a covalent M inhibitor was the first such approved therapy. Although M inhibitors of various chemical classes have been reported, they are generally less active against nirmatrelvir-resistant variants and have limited pan-coronavirus potential, presenting a significant human health risk upon future outbreaks. We here present a novel approach and utilized DNA-encoded chemical library screening to identify the noncovalent M inhibitor , which demonstrated a distinct binding mode to nirmatrelvir. A macrocyclization strategy designed to lock the active conformation resulted in lactone with significantly improved antiviral activity. Further optimization led to the potent lactam , which demonstrated exceptional potency against nirmatrelvir-resistant variants as well as against a panel of viral main proteases from other coronaviruses.

PubMed: 39453309
DOI: 10.1021/acs.jmedchem.4c02009

Experimental method

X-RAY DIFFRACTION (1.476 Å)