Lipid lowering natural products targeting hPCSK9 may prevent the severity of COVID-19 infection

Abstract

\n\nThe deadly outbreak of COVID-19 disease caused by novel SARS CoV2 has created an unprecedented global health crisis affecting every sectors of human life and enormous damage to world’s economy. With >60.3 million infections and >1.42 million deaths worldwide as of November 27, 2020, there is no treatment for this disease neither is there any available vaccine as yet. Serious research efforts are ongoing on all fronts including treatment, prevention and diagnosis to combat the spread of this infection. A number of targets that include both viral and host proteins have been identified and became part of intense investigation. In this respect the viral surface spike (S) glycoprotein caught the attention most. It is cleaved by multiple host proteases to allow recognition by host receptor human Angiotensin Converting Enzyme2 (hACE2) leading to fusion and viral replication. Natural products, small compounds, antioxidants, peptides, proteins, oligonucleotides, antibodies and other compounds are under investigation for development of antiviral agents against COVID-19. Recently cholesterol lowering phytocompounds Quercetin, Swertiamarin and Berberine which promote Human Low Density Lipoprotein (hLDLR) via inhibition of Human Proprotein Convertase Subtilisin Kexin9 (hPCSK9) have been shown to block viral infections caused by ebola, influenza, Respiratory Syncytial Virus (RSV), Hepatitis C virus (HCV) and other RNA type viruses. Since SARS CoV2 is a RNA virus with similar genetic structure and infection machinery, it is hypothesised that these phytocompounds may also exhibit antiviral property against COVID-19. This concept is based on recently published studies as well as our herein presented in silico modeling and computational data. These results suggested strong interactions of hPCSK9 with above phytocompounds and most importantly with hACE2 following its complexation with receptor binding domain (RBD) of SARS CoV2 S protein. These outcomes and a proposed schematic model showing association of hPCSK9 with SARS CoV2 infection is presented in this manuscript. It is suggested that hPCSK9 performs the role of a co-receptor in binding with hACE2:RBD complex and thereby facilitates viral fusion. As a consequence PCSK9 inhibitors may provide beneficial effect against COVID-19 infection by slowing down viral fusion through displacement of bound hPCSK9 from the above complex. \n\n\n