9IZB

Crystal structure of SARS-CoV-2 main protease in complex with TMP1

This is a non-PDB format compatible entry.

Summary for 9IZB

• Entry DOI: 10.2210/pdb9izb/pdb
• Descriptor: 3C-like proteinase nsp5, TMP1 (3 entities in total)
• Functional Keywords: severe acute respiratory syndrome coronavirus 2, main protease, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 2
• Total formula weight: 34544.78

Authors

Deng, X.Y.,Zeng, R.,Yang, S.Y.,Lei, J. (deposition date: 2024-08-01, release date: 2025-05-28, Last modification date: 2025-12-10)

Primary citation

Shuai, H.,Qiao, J.,Yoon, C.,Zhang, G.,Hou, Y.,Xia, X.,Wang, L.,Deng, X.,Wang, Y.,Li, Q.,Du, L.,Liu, Y.,Zhou, M.,Wong, H.T.,Hu, J.,Liu, H.,Hu, B.,Wang, D.,Su, J.,Pan, Y.,Ye, Y.,Chen, Y.,Fang, Z.,Xia, Z.,Chai, Y.,Shi, J.,Wang, Y.,Zhu, T.,Zhang, H.,Yuan, S.,Zhou, J.,Chan, J.F.,Yuen, K.Y.,Xu, C.,Lei, J.,Yang, S.,Chu, H.
An orally available M pro /TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo.
Nat Commun, 16:6541-6541, 2025

PubMed Abstract: Coronaviruses have caused three major endemics in the past two decades. Alarmingly, recent identification of novel zoonotic coronaviruses that caused human infections suggests the risk of future coronavirus outbreak caused by spillover infection from animal reservoirs remains high. Therefore, development of alternative therapeutic options with broad-spectrum anti-coronavirus activities are urgently needed. Here, we develop an orally available bispecific inhibitor, TMP1, which simultaneously targets key coronavirus replication protease M and the essential airway protease TMPRSS2. TMP1 shows broad-spectrum protection not only against different SARS-CoV-2 variants but also against multiple human-pathogenic coronaviruses in vitro. By using the K18-hACE2 transgenic mouse, hDPP4 knock-in mouse and golden Syrian hamster models, we demonstrate TMP1 cross-protects against highly-pathogenic coronaviruses (SARS-CoV-1, SARS-CoV-2 and MERS-CoV) in vivo and efficiently abrogates SARS-CoV-2 transmission. Through structural and mutagenesis studies, we confirm the direct interaction of TMP1 with M and TMPRSS2, and pinpoint the key sites of interactions. Importantly, TMP1 inhibits the infection of nirmatrelvir-resistant SARS-CoV-2 escape mutants. Together, our findings demonstrate the antiviral potential of the bispecific M/TMPRSS2 antiviral design against human-pathogenic coronaviruses and other emerging coronaviruses.

PubMed: 40670362
DOI: 10.1038/s41467-025-60832-z

Experimental method

X-RAY DIFFRACTION (2.6 Å)