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Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L.
Costanzi, Elisa; Kuzikov, Maria; Esposito, Francesca; Albani, Simone; Demitri, Nicola; Giabbai, Barbara; Camasta, Marianna; Tramontano, Enzo; Rossetti, Giulia; Zaliani, Andrea; Storici, Paola.
  • Costanzi E; Elettra-Sincrotrone Trieste, 34149 Trieste, Italy.
  • Kuzikov M; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), 22525 Hamburg, Germany.
  • Esposito F; Department of Life Sciences and Chemistry, Jacobs University Bremen GmbH, 28759 Bremen, Germany.
  • Albani S; Department of Life and Environmental Sciences, University of Cagliari, 09124 Cagliari, Italy.
  • Demitri N; Institute for Neuroscience and Medicine (INM-9) and Institute for Advanced Simulations (IAS-5) "Computational Biomedicine", Forschungszentrum Jülich, 52425 Jülich, Germany.
  • Giabbai B; Department of Biology, Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen University, 52062 Aachen, Germany.
  • Camasta M; Elettra-Sincrotrone Trieste, 34149 Trieste, Italy.
  • Tramontano E; Elettra-Sincrotrone Trieste, 34149 Trieste, Italy.
  • Rossetti G; Department of Life and Environmental Sciences, University of Cagliari, 09124 Cagliari, Italy.
  • Zaliani A; Department of Life and Environmental Sciences, University of Cagliari, 09124 Cagliari, Italy.
  • Storici P; Institute for Neuroscience and Medicine (INM-9) and Institute for Advanced Simulations (IAS-5) "Computational Biomedicine", Forschungszentrum Jülich, 52425 Jülich, Germany.
Int J Mol Sci ; 22(21)2021 Oct 29.
Article in English | MEDLINE | ID: covidwho-1488616
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Cathepsin L / Coronavirus 3C Proteases / SARS-CoV-2 / COVID-19 Drug Treatment / Leupeptins Type of study: Experimental Studies / Randomized controlled trials Limits: Humans Language: English Year: 2021 Document Type: Article Affiliation country: Ijms222111779

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Cathepsin L / Coronavirus 3C Proteases / SARS-CoV-2 / COVID-19 Drug Treatment / Leupeptins Type of study: Experimental Studies / Randomized controlled trials Limits: Humans Language: English Year: 2021 Document Type: Article Affiliation country: Ijms222111779