Between inhibitors and repurposed drugs: COVID19 pharmacological approaches based on virus pathological life cycle

Abstract

Commendable efforts are being invested to combat CoronaVIrus Disease-19 (COVID-19) through drug repurposing and developing an effective vaccine. Since the declaration of the outbreak of COVID19 by the WHO, scientists, researchers, and healthcare providers are collaborating worldwide to find a cure against the causative virus SARS CoV-2 through drug repurposing (also known as drug repositioning). The therapeutic inhibition of a virus infection involves several targets from various steps of the virus life cycle; such as receptor-binding, cell fusion, virus replication, and release of virions. Researchers have established that SARS CoV-1, MERS and SARS CoV-2 fuse with the host cell through their S spike. Two pathways of viral cell entry are proposed: TMPRSS2 dependent pathway and TMPRSS2-independent pathway. Researches also showed through in-silico studies that drugs could work similarly on them. According to a fusion-assay study in 2005 on SARS CoV-1 cell entry, Cathepsin protease L (CatL) induced viral entry in a pH dependant manner; the optimum being acidic pH (Lysosomes). A recent in-vitro study published in 2020, added that CatL continues S1 subunit degradation in the acidic endosome and lysosome compartments. Several studies have published possible candidates blocking the two pathways for virus cell-entry before its replication in the host. Clinical documentations over the past year have shown that the severity of SARS CoV-2 lingers beyond reducing viral load due to the inflammatory response resulting in a cytokine storm. Hence, we hereby take the opportunity to highlight that the use of Ulinastatin could greatly benefit moderate and severe cases of COVID19 and reduce mortality as an addition to a comprehensive protocol.