9X7F
Crystal structure of PDCoV 3CL protease (3CLpro) in complex with compound 1
This is a non-PDB format compatible entry.
Summary for 9X7F
| Entry DOI | 10.2210/pdb9x7f/pdb |
| Descriptor | 3C-like protease, (2~{S})-~{N}-[(2~{S})-1-azanylidene-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]-2-[[(2~{S})-3,3-dimethyl-2-[2,2,2-tris(fluoranyl)ethanoylamino]butanoyl]amino]-4-methyl-pentanamide (3 entities in total) |
| Functional Keywords | protease, mpro, viral protein-inhibitor complex, viral protein |
| Biological source | Porcine deltacoronavirus |
| Total number of polymer chains | 6 |
| Total formula weight | 206700.97 |
| Authors | |
| Primary citation | Su, H.,Nie, T.,Chen, G.,Xiong, M.,Zhang, Y.,Wu, G.,You, M.,Xie, H.,He, J.,Xiong, Y.,Hu, H.,Zhao, W.,Li, M.,Xiao, G.,Zhang, L.,Xu, Y. Structure-Based Development of Ultra-Broad-Spectrum 3C-Like Protease Inhibitors. Adv Sci, :e12342-e12342, 2025 Cited by PubMed Abstract: Recurrence of coronavirus outbreaks and zoonotic origins of human coronaviruses underscore the importance of developing pan-coronavirus antivirals. The highly conserved 3C-like protease (3CL) in coronaviruses, together with the well-established druggability, makes it an ideal target for broad-spectrum antiviral therapeutics. Here, the inhibitory activity of approved 3CL inhibitors, including nirmatrelvir, ensitrelvir, and simnotrelvir, against fifteen 3CLs is first reported by enzymatic assays. Despite their potent inhibition toward 3CLs of β-CoVs, these inhibitors show reduced potency against 3CLs from the other three genera, particularly against two newly identified human coronaviruses (α-CCoV-HuPn-2018 and δ-PDCoV). In this context, continued efforts in structure-based optimization of nirmatrelvir lead to the identification of compound 8 that potently inhibits a panel of 32 3CLs across all subgenera (ICs: 19-146 nm), with an IC value of 61 and 81 nm against α-CCoV-HuPn-2018 and δ-PDCoV 3CLs, respectively. Moreover, it effectively inhibits nirmatrelvir-resistant 3CL mutants and demonstrates broad-spectrum antiviral efficacy in cells. These findings suggest an important rule that a small, non-cyclic P2 segment and a P4 segment with a suitable size are preferred by the design of ultra-broad-spectrum 3CL inhibitors, and provide a proof-of-concept guide for developing broad-spectrum antivirals as potential pan-CoV therapeutics. PubMed: 41388583DOI: 10.1002/advs.202512342 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.64 Å) |
Structure validation
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