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Instruments / Technical Area	Publication Details	Published	Actions
B21-High Throughput SAXS B23-Circular Dichroism	Stabilization of the dimeric state of SARS-CoV-2 main protease by GC376 and Nirmatrelvir Alessandro Paciaroni , Valeria Libera , Francesca Ripanti , Andrea Orecchini , Caterina Petrillo , Daniela Francisci , Elisabetta Schiaroli , Samuele Sabbatini , Anna Gidari , Elisa Bianconi , Antonio Macchiarulo , Rohanah Hussain , Lucia Silvestrini , Paolo Moretti , Norhan Belhaj , Matteo Vercelli , Yessica Roque , Paolo Mariani , Lucia Comez , Francesco Spinozzi International Journal Of Molecular Sciences 24 DOI: 10.3390/ijms24076062 Diamond Proposal Number(s): [29982, 32331] Open Access Show Abstract ▼ Abstract: The main protease (Mpro or 3CLpro) is an enzyme that is evolutionarily conserved among different genera of coronaviruses. As it is essential for processing and maturing viral polyproteins, Mpro has been identified as a promising target for the development of broad-spectrum drugs against coronaviruses. Like SARS-CoV and MERS-CoV, the mature and active form of SARS-CoV-2 Mpro is a dimer composed of identical subunits, each with a single active site. Individual monomers, however, have very low or no catalytic activity. As such, inhibition of Mpro can be achieved by molecules that target the substrate binding pocket to block catalytic activity or target the dimerization process. In this study, we investigated GC376, a transition-state analog inhibitor of the main protease of feline infectious peritonitis coronavirus, and Nirmatrelvir (NMV), an oral, bioavailable SARS-CoV-2 Mpro inhibitor with pan-human coronavirus antiviral activity. Our results show that both GC376 and NMV are capable of strongly binding to SARS-CoV-2 Mpro and altering the monomer-dimer equilibrium by stabilizing the dimeric state. This behavior is proposed to be related to a structured hydrogen-bond network established at the Mpro active site, where hydrogen bonds between Ser1’ and Glu166/Phe140 are formed in addition to those achieved by the latter residues with GC376 or NMV.	Mar 2023

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B21-High Throughput SAXS
B23-Circular Dichroism

Stabilization of the dimeric state of SARS-CoV-2 main protease by GC376 and Nirmatrelvir