Janus sword actions of chloroquine and hydroxychloroquine against COVID-19

Abstract

Chloroquine (CQ) and its analogue hydroxychloroquine (HCQ) have been thrust into our everyday vernacular because some believe, based on very limited basic and clinical data, that they might be helpful in preventing and/or lessening the severity of the pandemic coronavirus disease 2019 (COVID-19). However, lacking is a temperance in enthusiasm for their possible use as well as sufficient perspective on their effects and side-effects. CQ and HCQ have well-known properties of being diprotic weak bases that preferentially accumulate in acidic organelles (endolysosomes and Golgi apparatus) and neutralize luminal pH of acidic organelles. These primary actions of CQ and HCQ are responsible for their anti-malarial effects; malaria parasites rely on acidic digestive vacuoles for survival. Similarly, de-acidification of endolysosomes and Golgi by CQ and HCQ may block severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) integration into host cells because SARS-CoV-2 may require an acidic environment for its entry and for its ability to bud and infect bystander cells. Further, de-acidification of endolysosomes and Golgi may underly the immunosuppressive effects of these two drugs. However, modern cell biology studies have shown clearly that de-acidification results in profound changes in the structure, function and cellular positioning of endolysosomes and Golgi, in signaling between these organelles and other subcellular organelles, and in fundamental cellular functions. Thus, studying the possible therapeutic effects of CQ and HCQ against COVID-19 must occur concurrent with studies of the extent to which these drugs affect organellar and cell biology. When comprehensively examined, a better understanding of the Janus sword actions of these and other drugs might yield better decisions and better outcomes.

Keywords: COVID-19; Chloroquine; Endolysosome; Golgi; Hydroxychloroquine; de-acidification.

Fig. 1

CQ and HCQ de-acidify acidic organelles. Membrane bound vesicles in the endocytic pathway (early endosome, recycling endosome, late endosome, and lysosomes) and the biosynthetic secretory pathway (Golgi apparatus and secretory vesicles) all display varying degrees of acidity, and these vesicles rapidly acidify as they progress along the endocytic or secretory pathway. As diprotic weak bases, CQ and HCQ are taken up by cells and trapped in these acidic organelles, where they neutralize pH and alter their structure, function, and trafficking.

Fig. 2

Coronaviruses and organellar pH. SARS-CoV enters host cells via endocytosis and utilizes host cell machinery for replication. Once inside endosomes, SARS-CoV escapes from these organelles via pH- and cathepsin L-dependent mechanism. Following replication in the cytoplasm SARS-CoV may assemble and mature in trans-Golgi, from which it is released via secretary vesicles. By de-acidifying these acidic organelles, CQ and HCQ may block virus entry and affect post-translational modifications including the proteolysis and glycosylation of SARS-CoV.

Fig. 3

CQ and HCQ affect cytokine release. The classical pathway for cytokine secretion involves direct transport along trans Golgi secretory pathways to the extracellular space (eg. IL-10) or indirectly though recycling endosomes to the extracellular space (egs. TNFα, IL-6, and IL-10). The non-classical pathway for cytokine secretion involves transport of cytokines (eg. IL-1β) into autophagosomes and fusion with endosome and form amiphisome before being released into the extracellular space. By deacidifying endolysosomes and Golgi, CQ and HCQ could reduce the secretion of, for example, the proinflammatory cytokine TNF-α, IL-1β and IL-6.