Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19

Abstract

Coronaviruses (CoVs) are a group of enveloped, single-stranded positive genomic RNA viruses and some of them are known to cause severe respiratory diseases in human, including Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and the ongoing coronavirus disease-19 (COVID-19). One key element in viral infection is the process of viral entry into the host cells. In the last two decades, there is increasing understanding on the importance of the endocytic pathway and the autophagy process in viral entry and replication. As a result, the endocytic pathway including endosome and lysosome has become important targets for development of therapeutic strategies in combating diseases caused by CoVs. In this mini-review, we will focus on the importance of the endocytic pathway as well as the autophagy process in viral infection of several pathogenic CoVs inclusive of SARS-CoV, MERS-CoV and the new CoV named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and discuss the development of therapeutic agents by targeting these processes. Such knowledge will provide important clues for control of the ongoing epidemic of SARS-CoV-2 infection and treatment of COVID-19.

Drug repurposing screens reveal FDA approved drugs active against SARS-Cov-2

“…Both SARS-CoV-1 and -2 engage angiotensin-converting enzyme 2 (ACE2) as their plasma membrane receptor (20)(21)(22) . Upon binding, the viruses along with the receptor are endocytosed into the cell into a low pH endosomal compartment where there are proteases, including cathepsins, that can cleave Spike and allow for entry into the cytosol (23)(24)(25). Since cathepsins require a low pH for activity, chloroquine and its derivatives that neutralize this low pH can effectively block viral entry (23)(24)(25).…”

“…Upon binding, the viruses along with the receptor are endocytosed into the cell into a low pH endosomal compartment where there are proteases, including cathepsins, that can cleave Spike and allow for entry into the cytosol (23)(24)(25). Since cathepsins require a low pH for activity, chloroquine and its derivatives that neutralize this low pH can effectively block viral entry (23)(24)(25). Recent studies have also identified a plasma membrane-associated serine protease, TMPRSS2, is active against Spike, cleaving the protein extracellularly thereby bypassing the requirement for endosomal proteases (26)(27)(28).…”

The global battle against SARS-CoV-2 and COVID-19

“…Zheng indicated that SARS-CoV-2 is an emerging new coronavirus that causes a global threat, and summarized the key events occurred during the early outbreak, the basic characteristics of the pathogen, the signs and symptoms of the infected patients, the possible transmission pathways of the virus, the Zhou and Zhao pointed out the great importance of using therapeutic neutralizing antibodies (NAbs) to control the spread and re-emergence of SARS-CoV-2 and assert that the development of NAbs therefore should be a high priority in near future [5]. Yang and Shen discussed the implication of the endocytic pathway and autophagy in viral infection and how novel therapeutic approaches could be developed by targeting these processes for treatment of COVID-19 [6].…”

HMGB1: A Possible Crucial Therapeutic Target for COVID-19?

“…Interestingly, it has been recognized that HMGB1 regulates autophagy [10] and could potentially be a biomarker of acute lung injury [11]. Autophagy is one of the mechanisms involved in COVID-19 and is involved in viral entry and replication in cells, so targeting this pro-Street Horm Res Paediatr 2 DOI: 10.1159/000508291 cess has been suggested as a possible novel therapeutic strategy for COVID-19 [12].…”