Autophagy as an emerging target for COVID-19: lessons from an old friend, chloroquine

Abstract

During the last week of December 2019, Wuhan (China) was confronted with the first case of respiratory tract disease 2019 (coronavirus disease 2019, COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the rapid outbreak of the transmission (~3.64 million positive cases and high mortality as of 5 May 2020), the world is looking for immediate and better therapeutic options. Still, much information is not known, including origin of the disease, complete genomic characterization, mechanism of transmission dynamics, extent of spread, possible genetic predisposition, clinical and biological diagnosis, complete details of disease-induced pathogenicity, and possible therapeutic options. Although several known drugs are already under clinical evaluation with many in repositioning strategies, much attention has been paid to the aminoquinoline derivates, chloroquine (CQ) and hydroxychloroquine (HCQ). These molecules are known regulators of endosomes/lysosomes, which are subcellular organelles central to autophagy processes. By elevating the pH of acidic endosomes/ lysosomes, CQ/HCQ inhibit the autophagic process. In this short perspective, we discuss the roles of CQ/ HCQ in the treatment of COVID-19 patients and propose new ways of possible treatment for SARS-CoV-2 infection based on the molecules that selectivity target autophagy.

FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2 (COVID-19) therapy

“…As viral infection hijacks fundamental mechanisms of mammalian cell physiology ( Alavian et al, 2011 ; Yeganeh et al, 2015 ), besides potential vaccine development strategy, combination of antiviral treatment in the presence of targeting these pathways could have the highest rate of success on overcoming this COVID-19 pandemic. Among these mechanisms, autophagy and unfolded protein response (UPR) received the attention of many research groups and important commentary papers and suggestions have been recently published ( Shojaei et al, 2020a ; Bonam et al, 2020 ; Vallamkondu et al, 2020 ; Sureda et al, 2020 ). SARS-CoV-2 infection probably involves autophagy pathway like many other respiratory viral infections ( Yeganeh et al, 2018 , 2013 ).…”

“…SARS-CoV-2 infection probably involves autophagy pathway like many other respiratory viral infections ( Yeganeh et al, 2018 , 2013 ). Some useful adjuvant therapy strategies like chloroquine or statins has common effects including regulation of cytokine storm and inflammation and inhibition of autophagy flux ( Shojaei et al, 2020a ; Bonam et al, 2020 ; Shojaei et al, 2020b ). On the other hand, SARS-CoV-12 infection probably induces UPR in the infected cells as it significantly increases protein biosynthesis in the infected cells like other coronaviruses ( Sureda et al, 2020 ).…”

Highlights in the fight against COVID-19: does autophagy play a role in SARS-CoV-2 infection?

“…In fact, the study demonstrated that patients who received HCQ suffered from an elevated risk of receiving mechanical ventilation or death within 28 days [ 54 ]. COVID-19, autophagy, and autophagy-modifying drugs are further discussed in recent Autophagy commentaries by Bonam and colleagues [ 55 ], Brest et al . [ 56 ], and Tang et al .…”

Immune Modulation as a Therapeutic Option During the SARS-CoV-2 Outbreak: The Case for Antimalarial Aminoquinolines

“…CQ/HCQ impair endosome-lysosome fusion through proton capture and pH increase, resulting in decreased clathrin expression at the plasma membrane, an endosomal stasis sometimes compared to a traffic jam upstream the lysosomal compartment, an increase in the number of intracellular vacuoles and a general decrease in endocytic trafficking and membrane receptor recycling ( 8 , 23 , 24 ). Moreover, CQ/HCQ specifically downregulate plasma membrane expression of PICALM/CALM (phosphatidylinositol binding clathrin assembly lymphoid myeloid leukemia protein), a transmembrane protein involved in clathrin-mediated and probably also clathrin-independent endocytosis ( 8 ).…”