A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity


Publication type
Article
Language
English
Access rights
Restricted access
Appears in Collections:
Metrics
Abstract
The main protease Mpro of SARS-CoV-2 is a well-studied major drug target. Additionally, it has been linked to this virus’ pathogenicity, possibly through off-target effects. It is also an interesting diagnostic target. To obtain more data on possible substrates as well as to assess the enzyme’s primary specificity a two-step approach was introduced. First, Terminal Amine Isobaric Labeling of Substrates (TAILS) was employed to identify novel Mpro cleavage sites in a mouse lung proteome library. In a second step, using a structural homology model, the MM/PBSA variant MM/GBSA (Molecular Mechanics Poisson-Boltzmann/Generalized Born Surface Area) free binding energy calculations were carried out to determine relevant interacting amino acids. As a result, 58 unique cleavage sites were detected, including six that displayed glutamine at the P1 position. Furthermore, modeling results indicated that Mpro has a far higher potential promiscuity towards substrates than expected. The combination of proteomics and MM/PBSA modeling analysis can thus be useful for elucidating the specificity of Mpro, and thus open novel perspectives for the development of future peptidomimetic drugs against COVID-19, as well as diagnostic tools.
Reference
Gallo G, Barcick U, Coelho C, Salardani M, Camacho MF., Cajado-Carvalho D, et al. A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity. Peptides. 2022 May;in press:170814. doi:10.1016/j.peptides.2022.170814.
Link to cite this reference
https://repositorio.butantan.gov.br/handle/butantan/4377
Journal title
Issue Date
2022


Files in This Item:

Existing users please Login
1-s2.0-S0196978122000808-main.pdf
Description:
Size: 1.3 MB
Format: Adobe PDF
Embargoed until January 1, 2999    Request a copy
Show full item record

The access to the publications deposited in this repository respects the licenses from journals and publishers.