7UUG

SARS-CoV-2 Main Protease S144A (Mpro S144A) in Complex with ML1006a

Summary for 7UUG

• Entry DOI: 10.2210/pdb7uug/pdb
• Related: 7SET 7SF1 7SF3 7SFB 7SFH 7SFI 7SGH 7U92
• Descriptor: 3C-like proteinase nsp5, (1R,2S,5S)-N-{(2S,3R)-4-(azetidin-1-yl)-3-hydroxy-4-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: sarscov2, sars-cov-2, coronavirus, main protease, protease, mpro, s144a, mutant, resistance, 3c-like proteinase, cl3pro, inhibitor, complex, covalent, adduct, ml1006a, ketoamide, azetidine, peptidomimetic, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34432.63

Authors

Westberg, M.,Fernandez, D.,Lin, M.Z. (deposition date: 2022-04-28, release date: 2023-10-11, Last modification date: 2024-03-20)

Primary citation

Westberg, M.,Su, Y.,Zou, X.,Huang, P.,Rustagi, A.,Garhyan, J.,Patel, P.B.,Fernandez, D.,Wu, Y.,Hao, C.,Lo, C.W.,Karim, M.,Ning, L.,Beck, A.,Saenkham-Huntsinger, P.,Tat, V.,Drelich, A.,Peng, B.H.,Einav, S.,Tseng, C.K.,Blish, C.,Lin, M.Z.
An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations.
Sci Transl Med, 16:eadi0979-eadi0979, 2024

PubMed Abstract: Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 M more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.

PubMed: 38478629
DOI: 10.1126/scitranslmed.adi0979

Experimental method

X-RAY DIFFRACTION (2 Å)