Structural Basis for coronaviral main proteases Inhibition by a 3CL Protease Inhibitor- GC376
The main protease (M ) of coronaviruses participates in viral replication, serving as a hot target for drug design. GC376 is able to effectively inhibit the activity of M , which is due to nucleophilic addition of GC376 by binding covalently with Cys145 in M active site. Here, we used fluorescence r...
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Published in | Journal of molecular biology p. 168474 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Netherlands
02.02.2024
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Subjects | |
Online Access | Get full text |
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Summary: | The main protease (M
) of coronaviruses participates in viral replication, serving as a hot target for drug design. GC376 is able to effectively inhibit the activity of M
, which is due to nucleophilic addition of GC376 by binding covalently with Cys145 in M
active site. Here, we used fluorescence resonance energy transfer (FRET) to analyze the IC
values of GC376 against M
s from six different coronaviruses (SARS-CoV-2, HCoV-229E, HCoV-HUK1, MERS-CoV, SARS-CoV, HCoV-NL63) and five M
mutants (G15S, M49I, K90R, P132H, S46F) from SARS-CoV-2 variants. The results showed that GC376 displays effective inhibition to various coronaviral M
s and SARS-CoV-2 M
mutants. In addition, the crystal structures of SARS-CoV-2 M
(wide type)-GC376, SARS-CoV M
-GC376, MERS-CoV M
-GC376, and SARS-CoV-2 M
mutants (G15S, M49I, S46F, K90R, and P132H)-GC376 complexes were solved. We found that GC376 is able to fit into the active site of M
s from different coronaviruses and different SARS-CoV-2 variants properly. Detailed structural analysis revealed key molecular determinants necessary for inhibition and illustrated the binding patterns of GC376 to these different M
s. In conclusion, we not only proved the inhibitory activity of GC376 against different M
s including SARS-CoV-2 M
mutants, but also revealed the molecular mechanism of inhibition by GC376, which will provide scientific guidance for the development of broad-spectrum drugs against SARS-CoV-2 as well as other coronaviruses. |
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ISSN: | 1089-8638 |