CQ, HCQ are protonated to CQ2+, HCQ2+

Stable Identifier
Reaction [transition]
Homo sapiens
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Chloroquine (CQ) and hydroxychloroquine (HCQ) are diprotic weak bases that can exist in both protonated and unprotonated forms. Unprotonated CQ or HCQ can diffuse freely and rapidly across the membranes of cells and organelles to acidic cytoplasmic vesicles (late endosomes and lysosomes). Agents that have this ability are known as lysosomotropic agents. Once protonated, CQ2+ or HCQ2+ are trapped in the acidic lumen of these vesicles. This leads to an irreversible accumulation of CQ or HCQ in acidic vesicles to concentrations as much as 100 fold over cytosolic ones and to an elevation of vesicle pH due to trapping of H+ ions by CQ or HCQ. Thus, CQ analogues interfere with endosomal and lysosomal acidification, which in turn inhibits proteolysis, chemotaxis, phagocytosis and antigen presentation. As a result, cells are not able to proceed with endocytosis, exosome release and phagolysosomal fusion in an orderly manner (Foley & Tilley 1998, Yang & Shen 2020). In vitro, these endosomal acidification fusion inhibitors block cellular infection by a clinical isolate of SARS-CoV-2 (Wang et al. 2020, Hu et al. 2020).

Literature References
PubMed ID Title Journal Year
32226290 Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19

Shen, HM, Yang, N

Int. J. Biol. Sci. 2020
28596841 Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases

Al-Bari, MAA

Pharmacol Res Perspect 2017
25693996 Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases

Al-Bari, MA

J. Antimicrob. Chemother. 2015
32145363 Chloroquine and hydroxychloroquine as available weapons to fight COVID-19

Raoult, D, Colson, P, Lagier, JC, Rolain, JM, Brouqui, P

Int. J. Antimicrob. Agents 2020
9719345 Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents

Tilley, L, Foley, M

Pharmacol. Ther. 1998
16115318 Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Nichol, ST, Benjannet, S, Seidah, NG, Bergeron, E, Rollin, PE, Ksiazek, TG, Vincent, MJ, Erickson, BR

Virol. J. 2005
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