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.
Highlights
After more than one and a half years since its first isolation (December 2019) [1] coronavirus SARS-Cov-2 is still threatening world health and has dramatically hampered the lifestyle on a global level
After the first round of induced fit docking, two main orientations of MG-132 in the binding pocket were observed: orientation A where the benzyloxycarbonyl of MG-132 interacts with residues Leu70, Met71, Ala136, and
The formation of a covalent bond between MG-132 was further investigated by performing covalent docking
Summary
After more than one and a half years since its first isolation (December 2019) [1] coronavirus SARS-Cov-2 is still threatening world health and has dramatically hampered the lifestyle on a global level. The large RNA-genome of SARS-CoV-2 codes for about 16 non-structural proteins, including the 3C-Like or main protease (Mpro; nsp5), the papain-like protease (PLpro; nsp3), the RNAdependent RNA polymerase (RdRp; nsp12), the helicase (Hel; nsp13), two methyltransferases (guanine-N7-methyltransferase with exoribonuclease activity; nsp and nucleoside-2’-Omethyltransferase; nsp16) and four structural proteins (spike (S), envelope (E), membrane (M) and nucleocapsid (N) protein) [3]. Each of these proteins represents a target for the development of antiviral drugs. The first Mpro inhibitor (PF-7304814) has entered clinical trials in March 2021 [5,6] together with other protease inhibitors like the DPP1 inhibitor Brensocatib [7] or like the urokinase inhibitor Upamostat [8]
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