Lysosomotropic Action of Amantadine: Basis for Treatment of COVID-19

Abstract

SARS-coronavirus 2 is the causal agent of the COVID-19 outbreak. SARSCov- 2 entry into a cell is dependent upon binding of the viral Spike (S) protein to cellular receptor and on cleavage of the spike protein by the host cell proteases such as Cathepsin L and Cathepsin B (CTSL/B). They are crucial elements of lysosomal pathway and both enzymes are almost exclusively located in the lysosomes. CTSL disruption offers potential for CoVID-19 therapies. The mechanisms of disruption include: decreasing expression of CTSL, direct inhibition of CTSL activity and modification of the CTSL environment (increase pH in the lysosome). We have conducted a high throughput drug screen gene expression analysis to identify compounds with the capacity to downregulate the expression of CTSL/CTSB. One of the most significant results shown to downregulate the expression of the CTSL gene is Amantadine(10uM). We confirmed Amantadine’s lysosmal trapping capacity in an invitro Lysosomal Trapping Assay. In addition, to downregulating CTSL, Amantadine disrupts the lysosomal pathways, hence, interferes with the capacity of the virus to replicate. It acts as a lysosomotropic agent altering the CTSL functional environment. We propose that Amantadine could decrease the viral load in SARS-CoV-2 positive patients and as such it may serve as a potent therapeutic decreasing the replication and infectivity of the virus likely leading to better clinical outcomes. Clinical studies are currently needed to examine the therapeutic efficacy of Amantadine in COVID-19 infection.