9BOO

Crystal structure of MERS-CoV Nsp5 in complex with PF-07817883

9BOO の概要

• エントリーDOI: 10.2210/pdb9boo/pdb
• 分子名称: 3C-like proteinase nsp5, N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1Z,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-(trifluoromethyl)-L-prolinamide (3 entities in total)
• 機能のキーワード: pf-07817883, nsp5, main protease, mers-cov, viral protein
• 由来する生物種: Middle East respiratory syndrome-related coronavirus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33845.68

構造登録者

Chen, P.,Arutyunova, E.,Lemieux, M.J. (登録日: 2024-05-05, 公開日: 2024-08-07, 最終更新日: 2024-10-30)

主引用文献

Chen, P.,Van Oers, T.J.,Arutyunova, E.,Fischer, C.,Wang, C.,Lamer, T.,van Belkum, M.J.,Young, H.S.,Vederas, J.C.,Lemieux, M.J.
A Structural Comparison of Oral SARS-CoV-2 Drug Candidate Ibuzatrelvir Complexed with the Main Protease (M pro ) of SARS-CoV-2 and MERS-CoV.
Jacs Au, 4:3217-3227, 2024

PubMed Abstract: Ibuzatrelvir (1) was recently disclosed and patented by Pfizer for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has received fast-track status from the USA Food and Drug Administration (FDA) and has entered phase III clinical trials as a possible replacement for Paxlovid. Like nirmatrelvir (2) in Paxlovid, this orally active drug candidate is designed to target viral main proteases (M) through reversible covalent interaction of its nitrile warhead with the active site thiol of the chymotrypsin-like cysteine protease (3CL protease). Inhibition of M hinders the processing of the proteins essential for viral replication . However, ibuzatrelvir apparently does not require ritonavir (3), which is coadministered in Paxlovid to block human oxidative metabolism of nirmatrelvir. Here, we report the crystal structure of the complex of ibuzatrelvir with the active site of SARS-CoV-2 M at 2.0 Å resolution. In addition, we show that ibuzatrelvir also potently inhibits the M of Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is fortunately not widespread but can be dangerously lethal (∼36% mortality). Co-crystal structures show that the binding mode of the drug to both active sites is similar and that the trifluoromethyl group of the inhibitor fits precisely into a critical S2 substrate binding pocket of the main proteases. However, our results also provide a rationale for the differences in potency of ibuzatrelvir for these two proteases due to minor differences in the substrate preferences leading to a weaker H-bond network in MERS-CoV M. In addition, we examined the reversibility of compound binding to both proteases, which is an important parameter in reducing off-target effects as well as the potential immunogenicity. The crystal structures of the ibuzatrelvir complexes with M of SARS-CoV-2 and of MERS-CoV will further assist drug design for coronaviral infections in humans and animals.

PubMed: 39211604
DOI: 10.1021/jacsau.4c00508

実験手法

X-RAY DIFFRACTION (1.5 Å)