Journal Article

FZJ-2021-04067

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L

Costanzi, E. ; Kuzikov, M. ; Esposito, F. ; Albani, S.FZJ* ; Demitri, N. ; Giabbai, B. ; Camasta, M. ; Tramontano, E. ; Rossetti, G. (Corresponding author)FZJ* ; Zaliani, A. ; Storici, P. (Corresponding author)

2021
Molecular Diversity Preservation International Basel

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Please use a persistent id in citations: http://hdl.handle.net/2128/28871  doi:10.3390/ijms222111779

Abstract: 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.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Jülich Supercomputing Center (JSC)
3. Computational Biomedicine (INM-9)

Research Program(s):

1. 5252 - Brain Dysfunction and Plasticity (POF4-525) (POF4-525)
2. 5111 - Domain-Specific Simulation & Data Life Cycle Labs (SDLs) and Research Groups (POF4-511) (POF4-511)

Appears in the scientific report 2021

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