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Therapeutic Potential of Exploiting Autophagy Cascade Against Coronavirus Infection.

ABSTRACT: Since its emergence in December 2019 in Wuhan, China, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) created a worldwide pandemic of coronavirus disease (COVID-19) with nearly 136 million cases and approximately 3 million deaths. Recent studies indicate that like other coronaviruses, SARS-CoV-2 also hijacks or usurps various host cell machineries including autophagy for its replication and disease pathogenesis. Double membrane vesicles generated during initiation of autophagy cascade act as a scaffold for the assembly of viral replication complexes and facilitate RNA synthesis. The use of autophagy inhibitors - chloroquine and hydroxychloroquine initially appeared to be as a potential treatment strategy of COVID-19 patients but later remained at the center of debate due to high cytotoxic effects. In the absence of a specific drug or vaccine, there is an urgent need for a safe, potent as well as affordable drug to control the disease spread. Given the intricate connection between autophagy machinery and viral pathogenesis, the question arises whether targeting autophagy pathway might show a path to fight against SARS-CoV-2 infection. In this review we will discuss about our current knowledge linking autophagy to coronaviruses and how that is being utilized to repurpose autophagy modulators as potential COVID-19 treatment.

SUBMITTER: Maity S

PROVIDER: S-EPMC8160449 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Tuberculosis (TB), a bacterialinfectious disease caused by Mycobacterium tuberculosis (M.tb), which causes significant mortality in humans worldwide. Current treatment regimen involve the administration of multiple antibiotics over the course of several months that contributes to patient non-compliance leading to relapse and the development of drug-resistant M.tb (MDR and XDR) strains. Together, these facts highlight the need for the development of shorter TB treatment regimens. Host-directed therapy (HDT) is a new and emerging concept that aims to augment host immune response using drugs/compounds with or without adjunct antibiotics against M.tb infection. Autophagy is a natural catabolic mechanism of the cell that involves delivering the cytosolic constituents to the lysosomes for degradation and recycling the components; thereby maintaining the cellular and energy homoeostasis of a cell. However, over the past decade, an improved understanding of the role of autophagy in immunity has led to autophagy activation by using drugs or agents. This autophagy manipulation may represent a promising host-directed therapeutic strategy for human TB. However, current clinical knowledge on implementing autophagy activation by drugs or agents, as a stand-alone HDT or as an adjunct with antibiotics to treat human TB is insufficient. In recent years, many reports on high-throughput drug screening and measurement of autophagic flux by fluorescence, high-content microscopy, flow cytometry, microplate reader and immunoblotting have been published for the discovery of drugs that modulate autophagy. In this review, we discuss the commonly used chemical screening approaches in mammalian cells for the discovery of autophagy activating drugs against M.tbinfection. We also summarize the various autophagy-activating agents, both pre-clinical candidates and compounds approved for advanced clinical investigation during mycobacterial infection. Finally, we discuss the opportunities and challenges in using autophagy activation as HDT strategy to improve TB outcome and shorten treatment regimen.

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Therapeutic Potential of Exploiting Autophagy Cascade Against Coronavirus Infection.

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