Preprint Review Version 2 Preserved in Portico This version is not peer-reviewed

Widely Available Lysosome Targeting Agents Should Be Considered as a Potential Therapy for COVID-19

Jan Homolak
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Ivan Kodvanj
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Version 1 : Received: 21 March 2020 / Approved: 23 March 2020 / Online: 23 March 2020 (07:28:51 CET)
Version 2 : Received: 23 March 2020 / Approved: 24 March 2020 / Online: 24 March 2020 (06:26:54 CET)

A peer-reviewed article of this Preprint also exists.

Abstract

While the COVID-19 pandemic advances, the scientific community struggles in the search for treatments. Several improvements have been made, including the discovery of clinical efficacy of chloroquine (CQ) in COVID-19 patients, but the effective treatment protocols are still missing. In order to find novel treatment options many scientists utilize the in silico approach to identify compounds that could interfere with the key molecules involved in entrance, replication, or dissemination of the SARS-CoV-2. However, most of the identified molecules are currently not available as pharmacological agents, and assessing their safety and efficacy could take many months. Here, we took a different approach based on the proposed pharmacodynamic model of CQ in COVID-19. The main mechanism of action responsible for the favourable outcome of COVID-19 patients treated with CQ seems to be related to pH modulation-mediated effect on the endolysosomal trafficking, a characteristic of chemical compounds often called lysosomotropic agents because of the physico-chemical properties that enable them to passively diffuse through the endosomal membrane and undergo protonation-based trapping in the lumen of the acidic vesicles. In this review, we discuss lysosomotropic and lysosome targeting drugs that are already in clinical use and are characterized by good safety profiles, low cost, and wide availability. We emphasize that some of these drugs, in particular azithromycin and other macrolide antibiotics, indomethacin and some other non-steroidal anti-inflammatory drugs, proton pump inhibitors, and fluoxetine could provide additional therapeutic benefits in addition to the potential antiviral effect that still has to be confirmed by well-controlled clinical trials. As some of these drugs, mostly antibiotics, were already empirically used in the treatment of COVID-19, we encourage our colleagues all over the world to publish patient data so potential efficacy of these agents can be evaluated in the clinical context and rapidly implemented in the therapeutic protocols if the beneficial effect on clinical outcome is observed.

Keywords

COVID-19; lysosomotropic agents; endosome; antiviral; drug repurposing

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Comments (1)

Comment 1
Received: 24 March 2020
Commenter: Jan Homolak
Commenter's Conflict of Interests: Author
Comment: We modified the title and several sentences in the text to better reflect the physicochemical properties of the drugs as not all drugs mentioned in the text have lipophilic and weakly basic properties (some interact with the lysosomal system in different ways, such as V-ATPase inhibition), and some might argue they shouldn't be referred to as lysosomotropic per se. These drugs still might show endolysosomal pH-mediated antiviral effects, and should therefore be mentioned in context of potential treatment for COVID-19. For this reason, in version 2 of our preprint, we rather call them "lysosome targeting drugs". Morover, we extended the section on potential effects of macrolies in COVID-19 and added a comment on their inhalatory formulations that could be considered as a treatment option in the future. Inhaled macrolides could provide antiviral and anti-inflammatory during the acute stage of the disease, and reduce potential consequences in terms of reduced lung function with restrictive pattern reported in patients that recovered from the disease. Inhalatory macrolide formulations have never been mentioned in this context so far, so we believe this has to be mentioned.
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