Amantadine disrupts lysosomal gene expression: A hypothesis for COVID19 treatment

Int J Antimicrob Agents. 2020 Jun;55(6):106004. doi: 10.1016/j.ijantimicag.2020.106004. Epub 2020 Apr 30.

Abstract

SARS-coronavirus 2 is the causal agent of the COVID-19 outbreak. SARS-Cov-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 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 affecting the conditions of CTSL environment (increase pH in the lysosomes). We have conducted a high throughput drug screen gene expression analysis to identify compounds that would downregulate the expression of CTSL/CTSB. One of the top significant results shown to downregulate the expression of the CTSL gene is amantadine (10uM). Amantadine was approved by the US Food and Drug Administration in 1968 as a prophylactic agent for influenza and later for Parkinson's disease. It is available as a generic drug. Amantadine in addition to downregulating CTSL appears to further disrupt lysosomal pathway, hence, interfering with the capacity of the virus to replicate. It acts as a lysosomotropic agent altering the CTSL functional environment. We hypothesize 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 will be needed to examine the therapeutic utility of amantadine in COVID-19 infection.

MeSH terms

  • Amantadine / therapeutic use*
  • Antiviral Agents / therapeutic use*
  • Betacoronavirus / drug effects*
  • COVID-19
  • COVID-19 Drug Treatment
  • Cathepsin B / metabolism
  • Cathepsin L / genetics
  • Cathepsin L / metabolism*
  • Cell Line
  • Coronavirus Infections / drug therapy*
  • Down-Regulation / drug effects
  • Humans
  • Lysosomes / metabolism
  • Pandemics
  • Pneumonia, Viral / drug therapy*
  • SARS-CoV-2

Substances

  • Antiviral Agents
  • Amantadine
  • Cathepsin B
  • CTSL protein, human
  • Cathepsin L