TY  - JOUR
AU  - Costanzi, Elisa
AU  - Kuzikov, Maria
AU  - Esposito, Francesca
AU  - Albani, Simone
AU  - Demitri, Nicola
AU  - Giabbai, Barbara
AU  - Camasta, Marianna
AU  - Tramontano, Enzo
AU  - Rossetti, Giulia
AU  - Zaliani, Andrea
AU  - Storici, Paola
TI  - Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L
JO  - International journal of molecular sciences
VL  - 22
IS  - 21
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - FZJ-2021-04067
SP  - 11779 -
PY  - 2021
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 34769210
UR  - <Go to ISI:>//WOS:000721074900001
DO  - DOI:10.3390/ijms222111779
UR  - https://juser.fz-juelich.de/record/902158
ER  -