Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L
After almost two years from its first evidence, the COVID-19 pandemic continues to afflict people worldwide, highlighting the need for multiple antiviral strategies. SARS-CoV-2 main protease (Mpro/3CLpro) is a recognized promising target for the development of effective drugs. Because single target...
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2021
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oai:doaj.org-article:402a115ac6144f37ac9ec633532be9742021-11-11T17:13:52ZStructural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L10.3390/ijms2221117791422-00671661-6596https://doaj.org/article/402a115ac6144f37ac9ec633532be9742021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11779https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067After almost two years from its first evidence, the COVID-19 pandemic continues to afflict people worldwide, highlighting the need for multiple antiviral strategies. SARS-CoV-2 main protease (Mpro/3CLpro) is a recognized promising target for the development of effective drugs. Because single target inhibition might not be sufficient to block SARS-CoV-2 infection and replication, multi enzymatic-based therapies may provide a better strategy. Here we present a structural and biochemical characterization of the binding mode of MG-132 to both the main protease of SARS-CoV-2, and to the human Cathepsin-L, suggesting thus an interesting scaffold for the development of double-inhibitors. X-ray diffraction data show that MG-132 well fits into the Mpro active site, forming a covalent bond with Cys145 independently from reducing agents and crystallization conditions. Docking of MG-132 into Cathepsin-L well-matches with a covalent binding to the catalytic cysteine. Accordingly, MG-132 inhibits Cathepsin-L with nanomolar potency and reversibly inhibits Mpro with micromolar potency, but with a prolonged residency time. We compared the apo and MG-132-inhibited structures of Mpro solved in different space groups and we identified a new apo structure that features several similarities with the inhibited ones, offering interesting perspectives for future drug design and in silico efforts.Elisa CostanziMaria KuzikovFrancesca EspositoSimone AlbaniNicola DemitriBarbara GiabbaiMarianna CamastaEnzo TramontanoGiulia RossettiAndrea ZalianiPaola StoriciMDPI AGarticleSARS-CoV-2Mpro/3CLProCathepsin-LpeptidomimeticsMG-132dual target inhibitorBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11779, p 11779 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
SARS-CoV-2 Mpro/3CLPro Cathepsin-L peptidomimetics MG-132 dual target inhibitor Biology (General) QH301-705.5 Chemistry QD1-999 |
| spellingShingle |
SARS-CoV-2 Mpro/3CLPro Cathepsin-L peptidomimetics MG-132 dual target inhibitor Biology (General) QH301-705.5 Chemistry QD1-999 Elisa Costanzi Maria Kuzikov Francesca Esposito Simone Albani Nicola Demitri Barbara Giabbai Marianna Camasta Enzo Tramontano Giulia Rossetti Andrea Zaliani Paola Storici Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L |
| description |
After almost two years from its first evidence, the COVID-19 pandemic continues to afflict people worldwide, highlighting the need for multiple antiviral strategies. SARS-CoV-2 main protease (Mpro/3CLpro) is a recognized promising target for the development of effective drugs. Because single target inhibition might not be sufficient to block SARS-CoV-2 infection and replication, multi enzymatic-based therapies may provide a better strategy. Here we present a structural and biochemical characterization of the binding mode of MG-132 to both the main protease of SARS-CoV-2, and to the human Cathepsin-L, suggesting thus an interesting scaffold for the development of double-inhibitors. X-ray diffraction data show that MG-132 well fits into the Mpro active site, forming a covalent bond with Cys145 independently from reducing agents and crystallization conditions. Docking of MG-132 into Cathepsin-L well-matches with a covalent binding to the catalytic cysteine. Accordingly, MG-132 inhibits Cathepsin-L with nanomolar potency and reversibly inhibits Mpro with micromolar potency, but with a prolonged residency time. We compared the apo and MG-132-inhibited structures of Mpro solved in different space groups and we identified a new apo structure that features several similarities with the inhibited ones, offering interesting perspectives for future drug design and in silico efforts. |
| format |
article |
| author |
Elisa Costanzi Maria Kuzikov Francesca Esposito Simone Albani Nicola Demitri Barbara Giabbai Marianna Camasta Enzo Tramontano Giulia Rossetti Andrea Zaliani Paola Storici |
| author_facet |
Elisa Costanzi Maria Kuzikov Francesca Esposito Simone Albani Nicola Demitri Barbara Giabbai Marianna Camasta Enzo Tramontano Giulia Rossetti Andrea Zaliani Paola Storici |
| author_sort |
Elisa Costanzi |
| title |
Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L |
| title_short |
Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L |
| title_full |
Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L |
| title_fullStr |
Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L |
| title_full_unstemmed |
Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L |
| title_sort |
structural and biochemical analysis of the dual inhibition of mg-132 against sars-cov-2 main protease (mpro/3clpro) and human cathepsin-l |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/402a115ac6144f37ac9ec633532be974 |
| work_keys_str_mv |
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