Tweet
HTML Code:
Pharmacol Res. 2020 May 13:104904. doi: 10.1016/j.phrs.2020.104904. [Epub ahead of print] The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis?
Roldan EQ1, Biasiotto G2,3, Magro P1, Zanella I2,3.
Author information
Abstract
The anti-malarial drugs chloroquine (CQ) and primarily the less toxic hydroxychloroquine (HCQ) are currently used to treat autoimmune diseases for their immunomodulatory and anti-thrombotic properties. They have also been proposed for the treatment of several viral infections, due to their anti-viral effects in cell cultures and animal models, and, currently, for the treatment of coronavirus disease 2019 (COVID-19), the pandemic severe acute respiratory syndrome caused by coronavirus 2 (Sars-Cov-2) infection that is spreading all over the world. Although in some recent studies a clinical improvement in COVID-19 patients has been observed, the clinical efficacy of CQ and HCQ in COVID-19 has yet to be proven with randomized controlled studies, many of which are currently ongoing, also considering pharmacokinetics, optimal dosing regimen, therapeutic level and duration of treatment and taking into account patients with different severity degrees of disease. Here we review what is currently known on the mechanisms of action of CQ and HCQ as anti-viral, anti-inflammatory and anti-thrombotic drugs and discuss the up-to-date experimental evidence on the potential mechanisms of action of CQ/HCQ in Sars-Cov2 infection and the current clinical knowledge on their efficacy in the treatment of COVID-19 patients. Given the role of iron in several human viral infections, we also propose a different insight into a number of CQ and HCQ pharmacological effects, suggesting a potential involvement of iron homeostasis in Sars-Cov-2 infection and COVID-19 clinical course.
? 2020 Elsevier Ltd. All rights reserved.
KEYWORDS:
ACE2, angiotensin-converting enzyme 2; APC, antigen-presenting cell; APS, anti-phospholipid syndrome; ARDS, acute respiratory distress syndrome; AnxA5, annexinA5; BMP/SMAD, bone morphogenetic/small mother against decapentaplegic; CME, clathrin-mediated endocytosis; COPD, chronic obstructive pulmonary disease; COVID-19; COVID-19, Sars-Cov-2 infection; CQ, Chloroquine; Chloroquine/hydroxychloroquine; DC, dendritic cell; DMT1, divalent metal-ion transporter 1; EE, early endosome; EPO, erythropoietin; ER, endoplasmic reticulum; ERFE, erythroferrone; ERGIC, endoplasmic reticulum-Golgi intermediate compartment; FPN1, ferroportin 1; FT, ferritin; HAEC, human aortic endotelial cell; HAMP, hepcidin; HCMV, Human Cytomegalovirus; HCQ, hydroxychloroquine; HCV, hepatitis C virus; HFE, hemochromatosis gene; HH, hemochromatosis; HIV-1, Human Deficiency Virus 1; HP, haptoglobin; HPX, hemopexin; HUVEC, human umbilical vein endothelial cell; ICU, intensive care unit; ID, iron deficiency; IDA, iron deficiency anemia; IDU, infectious disease unit; IFN-γ, interferon-γ; IFN1, type interferon; IL-12, interleukin-12; IL-13, interleukin-13; IL-17, interleukin-17; IL-1β, interleukin-1β; IL-4, interleukin-4; IL-6, interleukin-6; IgG, immunoglobulin G; Inflammation; Iron; JAK/STAT3, Janus kinase/signal transducers and activators of transcription 3; LEL, late endosome-lysosome; LF, lactoferrin; LPS, lipopolysaccharide; M, viral envelope membrane protein; MAPK, mitogen-activated protein kinase; MHC, Major Histocompatibility Complex; MHV-3, mouse hepatitis virus type 3; MMP, matrix metalloproteinase; MOI, multiplicity of infection; NET, neutrophil extracellular trap; NK, natural killer; NOX2, NADPH oxidase 2; NP, virus nucleoprotein; PICALM, phosphatidylinositol binding clathrin assembly protein; RA, rheumatoid arthritis; RBC, red blood cell; S, viral spike protein; SLE, systemic lupus erythematosus (SLE); STEAP3, metalloreductase six-transmembrane epithelial antigen of the prostate 3; Sars-Cov-2; TF, tissue factor; TFR1, transferrin receptor 1; TGN, trans-Golgi network; TGT, thrombin generating time; TLR, Toll-like receptor; TMPRSS2, transmembrane serine protease 2; TNF-α, tumor necrosis factor-α; TRPML1/MCOLN1, mucolipin 1; Th, T helper; Thrombosis; VCAM-1, vascular cellular adhesion molecule 1; aPL, anti-phospholipid; eNOS, endothelial nitric oxide synthetase; eNOX, endosomal NADPH oxidase; mAb, monoclonal antibody; β2GPI, β2-glicoprotein I
PMID:32405228PMCID:PMC7217799DOI:10.1016/j.phrs.2020.104904