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“Amantadine disrupts lysosomal gene expression; potential therapy for COVID19”

Sandra P. Smieszek, Bart P Przychodzen, Mihael H Polymeropoulos
doi: https://doi.org/10.1101/2020.04.05.026187
Sandra P. Smieszek
1Vanda Pharmaceuticals, 2200 Pennsylvania NW, Suite 300-E, Washington, DC 20037
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  • For correspondence: sps92@case.edu
Bart P Przychodzen
1Vanda Pharmaceuticals, 2200 Pennsylvania NW, Suite 300-E, Washington, DC 20037
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Mihael H Polymeropoulos
1Vanda Pharmaceuticals, 2200 Pennsylvania NW, Suite 300-E, Washington, DC 20037
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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 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. 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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 05, 2020.
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“Amantadine disrupts lysosomal gene expression; potential therapy for COVID19”
Sandra P. Smieszek, Bart P Przychodzen, Mihael H Polymeropoulos
bioRxiv 2020.04.05.026187; doi: https://doi.org/10.1101/2020.04.05.026187
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“Amantadine disrupts lysosomal gene expression; potential therapy for COVID19”
Sandra P. Smieszek, Bart P Przychodzen, Mihael H Polymeropoulos
bioRxiv 2020.04.05.026187; doi: https://doi.org/10.1101/2020.04.05.026187

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