This title appears in the Scientific Report :
2021
Please use the identifier:
http://dx.doi.org/10.3390/ijms222111779 in citations.
Please use the identifier: http://hdl.handle.net/2128/28871 in citations.
Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L
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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Personal Name(s): | Costanzi, Elisa |
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Kuzikov, Maria / Esposito, Francesca / Albani, Simone / Demitri, Nicola / Giabbai, Barbara / Camasta, Marianna / Tramontano, Enzo / Rossetti, Giulia (Corresponding author) / Zaliani, Andrea / Storici, Paola (Corresponding author) | |
Contributing Institute: |
Computational Biomedicine; IAS-5 Computational Biomedicine; INM-9 Jülich Supercomputing Center; JSC |
Published in: | International journal of molecular sciences, 22 (2021) 21, S. 11779 - |
Imprint: |
Basel
Molecular Diversity Preservation International
2021
|
DOI: |
10.3390/ijms222111779 |
Document Type: |
Journal Article |
Research Program: |
Domain-Specific Simulation & Data Life Cycle Labs (SDLs) and Research Groups Brain Dysfunction and Plasticity |
Link: |
OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://hdl.handle.net/2128/28871 in citations.
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. |