9L13

The crystal structure of SARS-CoV-2 Main protease in complex with an iso-quinoline-derived inhibitor FD6-31

This is a non-PDB format compatible entry.

Summary for 9L13

• Entry DOI: 10.2210/pdb9l13/pdb
• Descriptor: 3C-like proteinase, (5-chloranylspiro[1~{H}-2-benzofuran-3,4'-piperidine]-1'-yl)-isoquinolin-4-yl-methanone (3 entities in total)
• Functional Keywords: sars-cov-2, inhibitor, complex, main protease, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 33671.82

Authors

Zhong, B.S.,Luo, G.,Wang, G.,Lu, W.Y. (deposition date: 2024-12-13, release date: 2025-12-17, Last modification date: 2026-07-01)

Primary citation

Luo, G.,Wang, G.,Liao, C.,Zhong, B.,Fan, L.,Zhang, J.,Rao, J.,Zhang, J.,Wang, Z.,Luo, M.,Yan, Y.,Lu, L.,Xu, W.,Wu, F.,Gao, X.,Lu, W.
Next-generation inhibitors of SARS-CoV-2 M pro overcome the deficiencies of Paxlovid.
Nat Commun, 17:-, 2026

PubMed Abstract: It remains elusive to design peptidomimetic inhibitors of SARS-CoV-2 main protease (M) refractory to multiple deficiencies of Paxlovid (ritonavir-boosted nirmatrelvir), pertaining mainly to E166X mutations-conferred drug resistance and inherent pharmacokinetic limitations to nirmatrelvir. We identify via virtual screening an iso-quinoline P1 moiety in place of the traditional γ-lactam and design iso-quinoline-containing inhibitors with high affinity for M and its nirmatrelvir-resistant E166X mutants. Further optimization at P4 cultivates distinctive peptidomimetic inhibitors with drastically improved pharmacokinetic properties and significantly enhanced antiviral efficacy independent of ritonavir. Two such inhibitors, FD3-32 and FD3-36, also potent against SARS-CoV-1 and MERS-CoV M, are more effective as a monotherapy regimen than Paxlovid in reducing viral loads in vivo and protecting infected male mice from acute lung injury. Here, we report the discovery of next-generation SARS-CoV-2 M inhibitors that overcome the deficiencies of Paxlovid, promising efficacious antivirals critical for mitigating the current and future pandemics of coronaviruses.

PubMed: 41935038
DOI: 10.1038/s41467-026-71436-6

Experimental method

X-RAY DIFFRACTION (1.96 Å)