Development of broad-spectrum coronavirus antiviral agents acting as allosteric modulators of the host protein sigma-1

Research Units
The project will be carried out by the following research units (RU):
• RU1, coordinated by the PI (Dr. Mangiatordi) and located at the Institute of Crystallography of the National Research Council
(CNR-IC);
• RU2, coordinated by Prof. Carmen Abate and located at the Dipartimento di Farmacia – Scienze del Farmaco of the University of
Bari (UNIBA);
• RU3, coordinated by the co-PI (Prof. Raffaello Potestio) and located at the Dipartimento di Fisica of the University of Trento
(UNITN);
• RU4, coordinated by Prof. Agostino Marrazzo, located at the Dipartimento di Scienze del Farmaco e della Salute of the University of
Catania (UNICT).
Background
• Host interactions are crucial for coronaviruses replication;
Ministero dell’Università e della Ricerca
MUR – BANDO 2022
• Pan-viral disease mechanisms were revealed by comparing host-coronavirus protein interaction networks;
• Sigma-1 receptor (s1R) proved to be a crucial host dependency factor for SARS-CoV-1 and SARS-CoV-2 infection;
• PB28, a known s1R antagonist, showed significant antiviral activity against SARS-CoV-2 (IC90 = 0.28 μM);
• An expanded chemical library of active PB28 analogues (antiviral activity in the nM range) is currently in the hands of the
proponents;
• Preliminary data suggest the presence of an allosteric mechanism responsible for the observed antiviral activity, likely able to
affect the interaction with the viral protein NSP6.
Objectives
• To shed light on the link between s1R affinity and SARS-CoV-2 antiviral activity;
• To get information about the conformational changes in s1R upon ligand binding, likely responsible for the antiviral activity;
• To rationally design and develop allosteric s1R ligands with higher antiviral activity (tested on different strands and different
viruses), to be also tested in preclinical models;
• To get insights into the role of s1R into SARS-CoV-2 replication by means of coarse-grained molecular dynamics (MD) simulations
and small angle X-ray scattering (SAXS) studies.