%0 Journal Article
%A Costanzi, Elisa
%A Kuzikov, Maria
%A Esposito, Francesca
%A Albani, Simone
%A Demitri, Nicola
%A Giabbai, Barbara
%A Camasta, Marianna
%A Tramontano, Enzo
%A Rossetti, Giulia
%A Zaliani, Andrea
%A Storici, Paola
%T Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L
%J International journal of molecular sciences
%V 22
%N 21
%@ 1422-0067
%C Basel
%I Molecular Diversity Preservation International
%M FZJ-2021-04067
%P 11779 -
%D 2021
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ 34769210
%U <Go to ISI:>//WOS:000721074900001
%R 10.3390/ijms222111779
%U https://juser.fz-juelich.de/record/902158