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000902158 1001_ $$aCostanzi, Elisa$$b0
000902158 245__ $$aStructural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L
000902158 260__ $$aBasel$$bMolecular Diversity Preservation International$$c2021
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000902158 520__ $$aAfter almost two years from its first evidence, the COVID-19 pandemic continues to afflict people worldwide, highlighting the need for multiple antiviral strategies. SARS-CoV-2 main protease (Mpro/3CLpro) is a recognized promising target for the development of effective drugs. Because single target inhibition might not be sufficient to block SARS-CoV-2 infection and replication, multi enzymatic-based therapies may provide a better strategy. Here we present a structural and biochemical characterization of the binding mode of MG-132 to both the main protease of SARS-CoV-2, and to the human Cathepsin-L, suggesting thus an interesting scaffold for the development of double-inhibitors. X-ray diffraction data show that MG-132 well fits into the Mpro active site, forming a covalent bond with Cys145 independently from reducing agents and crystallization conditions. Docking of MG-132 into Cathepsin-L well-matches with a covalent binding to the catalytic cysteine. Accordingly, MG-132 inhibits Cathepsin-L with nanomolar potency and reversibly inhibits Mpro with micromolar potency, but with a prolonged residency time. We compared the apo and MG-132-inhibited structures of Mpro solved in different space groups and we identified a new apo structure that features several similarities with the inhibited ones, offering interesting perspectives for future drug design and in silico efforts.
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000902158 7001_ $$00000-0001-8771-1865$$aKuzikov, Maria$$b1
000902158 7001_ $$00000-0001-9725-7977$$aEsposito, Francesca$$b2
000902158 7001_ $$0P:(DE-Juel1)181061$$aAlbani, Simone$$b3
000902158 7001_ $$aDemitri, Nicola$$b4
000902158 7001_ $$aGiabbai, Barbara$$b5
000902158 7001_ $$aCamasta, Marianna$$b6
000902158 7001_ $$00000-0002-4849-0980$$aTramontano, Enzo$$b7
000902158 7001_ $$0P:(DE-Juel1)145921$$aRossetti, Giulia$$b8$$eCorresponding author
000902158 7001_ $$00000-0002-1740-8390$$aZaliani, Andrea$$b9
000902158 7001_ $$0P:(DE-HGF)0$$aStorici, Paola$$b10$$eCorresponding author
000902158 773__ $$0PERI:(DE-600)2019364-6$$a10.3390/ijms222111779$$gVol. 22, no. 21, p. 11779 -$$n21$$p11779 -$$tInternational journal of molecular sciences$$v22$$x1422-0067$$y2021
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