Targeting furin activity through in silico and in vitro drug repurposing strategy for SARS-CoV-2 spike glycoprotein cleavage repression

Abstract

In December 2019, a new coronavirus was identified in the Hubei province of central china and named SRAS-CoV-2. This new virus induces COVID-19, a severe respiratory disease with high death rate. The spike protein (S) of SARS-CoV-2 contains furin-like cleavage sites absent the other SARS-like viruses. The viral infection requires the priming or cleavage of the S protein and such processing seems essential for virus entry into the host cells. Furin is highly expressed in the lung tissue and the expression is further increased in lung cancer, suggesting the exploitation of this mechanism by the virus to mediate enhanced virulence as shown by the higher risk of COVID-19 in these patients. In this study, we used structure- based virtual screening and a collection of about 8,000 unique approved and investigational drugs suitable for docking to search for molecules that could inhibits furin activity. Sulconazole, a broad-spectrum anti-fungal agent, was found to be of potential interest. Using Western blot analysis, Sulconazole was found to inhibit the cleavage of the cell surface furin substrate MT1-MMP that contains two furin cleavage sites similar to those of the SARS- CoV-2 spike protein. Sulconazole and analogs could be interesting for repurposing studies and to probe the yet not fully understood molecular mechanisms involved in cell entry.

Computational study of pomegranate peel extract polyphenols as potential inhibitors of SARS-CoV-2 virus internalization

“…The results of our study confirmed that punicalin and punicalagin interacted with furin active site amino acid residues forming more stable complexes than sulconazole as a positive control. Sulconazole, a broad-spectrum anti-fungal agent, was found to be the most promising candidate with anti-furin activity from the collection of about 8000 molecules [53]. Contrary to the less significant results of binding energies achieved in docking analysis with the S glycoprotein and ACE2, ellagic and gallic acids formed stable complexes with furin revealing binding energies to be −7.801 and − 7.486 kcal/mol, respectively.…”

PAMAM–guanylthiourea conjugates mask furin's substrate binding site: mechanistic insights from molecular docking and molecular dynamics studies assist the design of potential furin inhibitors

“…[19][20][21][22] Even though surface modified PAMAM dendrimers were studied as antiviral agents, 23,24 molecular modelling studies of the PAMAM dendrimer with biological targets have received meagre attention, not to mention the gap in correlating the computational studies and experimental results. 25 Similarly, very few reports have attempted the in silico screening of novel molecules for furin inhibition, 26,27 specifically to understand the molecular level interactions at the catalytic site. Hence, we envisaged the design of a library of molecular conjugates comprising PAMAM and GTU units and explored their interactions within furin's catalytic pockets to decipher mechanistic insights and provide molecular level analysis of the resulting interactions.…”