A Promising Agent for Coronavirus SARS-CoV-2 Infection therapy: Orally Available - Highly Potent Integrin avb3/avb5 Inhibitor
Project ID : 47-2020-10889
Pneumonia caused by the new coronavirus SARS-CoV-2 has caused serious damage to people’s lives and health. The initial route of infection is the binding of the spike protein (S protein) of the virus to the angiotensin-converting enzyme 2 (ACE2). From bioinformatics analysis, it was found that the S protein of SARS-CoV-2 produced an evolutionary mutation of K403R compared with the S protein of SARS-CoV, forming an adjacent RGD motif at the interaction surface.
A wide array of viruses utilize integrins as receptors to mediate multiple functions such as viral entry and activation of signalling events. Integrins are integral membrane proteins that mediate a variety of functions including cell adhesion and signalling events. Integrins are arranged as heterodimers on the cell surface composed of two transmembrane subunits: an α and a β subunit. The integrin heterodimers have a large extracellular domain to mediate binding to ligands, such as extracellular membrane proteins, including fibronectin or vitronectin, either through the I- (or A) domain within the α subunit or through an interface formed by the β propeller domain of the α subunit with the I- domain of the β subunit. Oftentimes integrins recognize and bind to their ligands through short, linear integrin-binding motifs, such as the arginine–glycine–aspartic acid (RGD) motifs. Integrins have a short cytoplasmic domain that can elicit the activation of signalling pathways and can promote cytoskeletal rearrangement within the cells.
As the RGD motif is considered as a ligand for many cell surface integrins, Gilon and Hoffman propose that the binding of S protein of SARS-CoV-2 with integrins may facilitate the infection process of the virus. Therefore they performed high-throughput virtual screening by choosing the key residues of S protein interface of SARS-CoV-2 and the adjacent RGD motif as potential binding site, to search for the potential agents targeting interaction of S protein of SARS-CoV-2 with both ACE2 and integrins as potential therapeutic drugs.
It has already been shown that the Zika virus (ZIKV), a close relative of the coronavirus SARS-CoV-2, uses integrin avb5 to infect neural stem cells. Gilon and Hoffman have developed a highly potent, orally available integrin avb3/avb5 inhibitor.
They propose to test whether this inhibitor will block the entry, activation and signalling events used by the coronavirus SARS-CoV-2 for infection.
VP, Business Development, Healthcare
HUJI, Faculty of Science
The Institute of Chemistry
HUJI, School of Medicine - IMRIC
School of Pharmacy- Institute for Drug Research