7CBT

The crystal structure of SARS-CoV-2 main protease in complex with GC376

Summary for 7CBT

• Entry DOI: 10.2210/pdb7cbt/pdb
• Descriptor: 3C-like proteinase, (1S,2S)-2-({N-[(benzyloxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid (3 entities in total)
• Functional Keywords: sars-cov-2, main protease, gc376, complex, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 2
• Total formula weight: 74798.81

Authors

Shi, Y.,Peng, G. (deposition date: 2020-06-13, release date: 2020-09-02, Last modification date: 2024-10-30)

Primary citation

Shi, Y.,Shuai, L.,Wen, Z.,Wang, C.,Yan, Y.,Jiao, Z.,Guo, F.,Fu, Z.F.,Chen, H.,Bu, Z.,Peng, G.
The preclinical inhibitor GS441524 in combination with GC376 efficaciously inhibited the proliferation of SARS-CoV-2 in the mouse respiratory tract.
Emerg Microbes Infect, 10:481-492, 2021

PubMed Abstract: The unprecedented coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious threat to global public health. Development of effective therapies against SARS-CoV-2 is urgently needed. Here, we evaluated the antiviral activity of a remdesivir parent nucleotide analog, GS441524, which targets the coronavirus RNA-dependent RNA polymerase enzyme, and a feline coronavirus prodrug, GC376, which targets its main protease, using a mouse-adapted SARS-CoV-2 infected mouse model. Our results showed that GS441524 effectively blocked the proliferation of SARS-CoV-2 in the mouse upper and lower respiratory tracts via combined intranasal (i.n.) and intramuscular (i.m.) treatment. However, the ability of high-dose GC376 (i.m. or i.n. and i.m.) was weaker than GS441524. Notably, low-dose combined application of GS441524 with GC376 could effectively protect mice against SARS-CoV-2 infection via i.n. or i.n. and i.m. treatment. Moreover, we found that the pharmacokinetic properties of GS441524 is better than GC376, and combined application of GC376 and GS441524 had a synergistic effect. Our findings support the further evaluation of the combined application of GC376 and GS441524 in future clinical studies.

PubMed: 33691601
DOI: 10.1080/22221751.2021.1899770

Experimental method

X-RAY DIFFRACTION (2.346 Å)