An Integrated Strategy for the Fast Discovery of SARS-CoV-2 Main Protease (Mpro) Inhibitors
Proponente: Barbara Gatto
Importo finanziato: € 200.000

Gruppo di ricerca
Dipartimento di Scienze del Farmaco – DSF: Alice Sosic, Barbara Gatto, Mattia Sturlese, Stefano Moro
Dipartimento di Scienze Chimiche – DISC: Massimo Bellanda, Roberto Battistutta
Dipartimento di Medicina Molecolare – DMM: Cristiano Salata

Abstract:
Il team propone un dettagliato piano di lavoro che, dallo screening in silico fino all’analisi virologica pre-clinica, possa individuare un candidato per la successiva valutazione clinica. Il progetto rappresenta un intervento immediato nella ricerca scientifica sul COVID-19 e ha come obiettivi quelli di 1) progettare e analizzare inibitori della Mpro, 2) selezionare le molecole in base alla loro capacità di legarsi alla proteasi del virus, 3) accelerare il processo di sviluppo di un inibitore della proteasi virale, e 4) ottimizzare un candidato che possa raggiungere velocemente la fase clinica.

Repurposing FDA approved drugs to thwart Covid-19 infection of human airway epithelia: towards a poly-pharmacological therapy
Proponente: Giovanni Marzaro
Importo finanziato: € 100.000

Gruppo di ricerca
Dipartimento di Scienze del Farmaco – DSF: Giovanni Marzaro
Dipartimento di Medicina Molecolare – DMM: Paola Brun

Abstract:
We propose rational repurposing of already approved drugs that can interfere with the function of viral structural proteins. To achieve these goals, we propose a three-prone interdisciplinary approach. 1) Identify drugs that can interfere with essential viral protein functions that are instrumental in attachment to cells and/or intercellular propagation of the SARSCoV-2 by using computational screens of drug libraries. 2) Validate candidate drugs using isolated viral proteins. 3) Demonstrate that the selected drugs alone, and more effectively in combination, can suppress the infectivity of SARS-CoV-2 of human primary airways cell, thus suggesting a possible poly-pharmacological treatment protocol.

Cell shielding to REduce Sars-cov sPreading intO humaN boDy (RESPOND)
Proponente: Gianfranco Pasut
Importo finanziato: € 90.000

Gruppo di ricerca
Dipartimento di Scienze del Farmaco – DSF: Gianfranco Pasut, Sara De Martin, Antonella Grigoletto
Istituto Zooprofilattico Sperimentale delle Venezie: Calogero Terregino, Francesco Bonfante,
Dipartimento di Scienze Molecolari e Nanosistemi – Università Ca’ Foscari di Venezia: Alessandro Angelini

Abstract
It has been extensively demonstrated that the viral Spike (S) protein exploits the human Angiotensin-Converting Enzyme 2 (ACE2), a protein with the important physiological task of degrading angiotensin II, for entry and infection of the host cells. In light of this consideration, this RESPOND project has the aim of developing a molecule able to avoid SARS-CoV-2 cell entry by binding tightly to and shielding human ACE2. This approach will sterically prevent ACE interaction with the viral protein S, without affecting the physiological enzymatic activity of ACE2. To reach this goal, we will conjugate the polymer poly(ethylene glycol) (PEG) to different anti-ACE2 binding molecules, like monoclonal antibody derivatives, i.e. Fab’ moieties, sc-Fv fragments, or nanobodies. These conjugates will undergo a complete preclinical characterization. They will be initially screened in vitro for their ability to maintain the enzymatic activity of ACE2 and their ACE2-shielding behavior against the virus contact and infection. Finally, the most promising conjugates will be tested in animal models for in vivo safety and efficacy by aerosol administration and/or intravenous injection, with the final aim of selecting a lead compound that can be further considered for development.