TY - JOUR
T1 - A Proteomics-MM/PBSA Dual Approach for the Analysis of SARS-CoV-2 Main Protease Substrate Peptide Specificity
AU - Gallo, Gloria
AU - Barcick, Uilla
AU - Coelho, Camila
AU - Salardani, Murilo
AU - Camacho, Mauricio F.
AU - Cajado-Carvalho, Daniela
AU - Loures, Flavio V.
AU - Serrano, Solange M.T.
AU - Hardy, Leon
AU - Zelanis, Andre
AU - Wurtele, Martin
N1 - Gallo, G., Barcick, U., Coelho, C., Salardani, M., Camacho, M.F., Cajado-Carvalho, D., Loures, F. V., Serrano, S.M.T., Hardy, L., Zelanis, A., & Wurtele, M. (2022). A Proteomics-MM/PBSA Dual Approach for the Analysis of SARS-CoV-2 Main Protease Substrate Peptide Specificity. Peptides, 1-24. https://doi.org/10.1016/j.peptides.2022.170814
PY - 2022/1/1
Y1 - 2022/1/1
N2 - 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.
AB - 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.
KW - Proteomics, TAILS, Free energy calculations, MM/PBSA, COVID-19, Main protease
UR - https://digitalcommons.usf.edu/fac_publications/4128
UR - https://doi.org/10.1016/j.peptides.2022.170814
M3 - Article
JO - Default journal
JF - Default journal
ER -