Generic placeholder image



ISSN (Print): 2666-7967
ISSN (Online): 2666-7975

Mini-Review Article

Mechanism of Action of Chloroquine/Hydroxychloroquine for Covid-19 Infection

Author(s): Alberto Boretti*, Bimal Banik and Stefania Castelletto

Volume 2, Issue 6, 2021

Published on: 12 November, 2020

Article ID: e130621187910 Pages: 10

DOI: 10.2174/2666796701999201112125319


Background: The recent serious outbreak of Covid-19 has required urgent medical treatments for numerous patients. No clinically active vaccines or antiviral agents are available for Covid-19. According to several studies, Chloroquine (CQ) and Hydroxychloroquine (HCQ) have shown potential as Covid-19 antivirals, especially when administered with Azithromycin (AZM).

Objective: Here, we review the rationale behind this use. CQ/HCQ is effective against Covid-19 in- -vitro and in-vivo laboratory studies. Therapy in Covid-19 infected patients with CQ/HCQ is supported by evidence of trials and field experiences from multiple sources.

Methods: The relevant works are reviewed. The presence or absence of conflict of interest is weighed against the conclusions.

Results: CQ/HCQ has been used with success in mild cases or medium severity cases. No randomized controlled trial has, however, been conducted to support the safety and efficacy of CQ/HCQ and AZM for Covid-19. Prophylaxis with CQ/HCQ is more controversial but generally not having side effects and supported by pre-clinical studies. The mechanism of action against Covid-19 is unclear. More research is needed to understand the mechanisms of actions CQ/HCQ has against Covid-19 infection, and this requires investigations with nanoscale imaging of viral infection of host cells.

Conclusion: Most of the published works indicate CQ/HCQ is likely effective against Covid-19 infection, almost 100% in prophylaxis and mild to medium severity cases, and 60% in late infection cases. The percentage of positive works is larger if works conducted under a probable conflict of interest are excluded from the list.

Keywords: Covid-19, severe acute respiratory syndrome, antiviral, prophylaxis, hydroxychloroquine, chloroquine, azithromycin.

France24, 2020, Conquering the coronavirus: The most pressing goal for these researchers in Paris. 2020. Available from:
Markson S. Coronavirus NSW: Dossier lays out case against China bat virus program. 2020. Available from:
Project-evidence.github. Evidence SARS-CoV-2 emerged from a biological laboratory in Wuhan, China. 2020. Available from:
Menachery VD, Yount BL Jr, Debbink K, et al. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat Med 2015; 21(12): 1508-13.
[] [PMID: 26552008]
Ren W, Qu X, Li W, et al. Difference in receptor usage between severe acute respiratory syndrome (SARS) coronavirus and SARS-like coronavirus of bat origin. J Virol 2008; 82(4): 1899-907.
[] [PMID: 18077725]
Cao Y, Li L, Feng Z, et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov 2020; 6(1): 11.
[] [PMID: 32133153]
Riva L, Yuan S, Yin X, et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature 2020; 586(7827): 113-9.
[] [PMID: 32707573]
Zhang L, Liu Y. Potential interventions for novel coronavirus in China: A systematic review. J Med Virol 2020; 92(5): 479-90.
[] [PMID: 32052466]
Malic N. This scientist suggested a drug to treat Covid-19 'Fact checkers' branded him fake news. 2020. Available from:
France24. On FRANCE 24 and RFI, Senegal's Macky Sall continues to demand cancellation of Africa's debt. 2020. Available from:
Indian council for medical research. Recommendation for empiric use of hydroxychloroquine for prophylaxis of SARS-CoV-2 infection 2020.Recommendation for empiric use of hydroxychloroquine for prophylaxis of SARS-CoV-2 infection. 2020. Available from:
Hu TY, Frieman M, Wolfram J. Insights from nanomedicine into chloroquine efficacy against COVID-19. Nat Nanotechnol 2020; 15(4): 247-9.
[] [PMID: 32203437]
Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020; 14(1): 72-3.
[] [PMID: 32074550]
Zhu N, Zhang D, Wang W, et al. China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382(8): 727-33.
[] [PMID: 31978945]
Haładyj E, Sikora M, Felis-Giemza A, Olesińska M. Antimalarials - are they effective and safe in rheumatic diseases? Reumatologia 2018; 56(3): 164-73.
[] [PMID: 30042604]
Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: An old drug against today’s diseases? Lancet Infect Dis 2003; 3(11): 722-7.
[] [PMID: 14592603]
Keyaerts E, Li S, Vijgen L, et al. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother 2009; 53(8): 3416-21.
[] [PMID: 19506054]
Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2005; 2(1): 69.
[] [PMID: 16115318]
Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020; 6: 16.
[] [PMID: 32194981]
Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30(3): 269-71.
[] [PMID: 32020029]
Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020; 71(15): 732-9.
[] [PMID: 32150618]
Taccone FS, Gorham J, Vincent JL. Hydroxychloroquine in the management of critically ill patients with COVID-19: The need for an evidence base. Lancet Respir Med 2020; 8(6): 539-41.
[] [PMID: 32304640]
Owens B. Excitement around hydroxychloroquine for treating COVID-19 causes challenges for rheumatology. Lancet Rheumatology 2020; 2(5): e257.
[] [PMID: 32368738]
Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines against coronavirus disease 2019 (COVID-19): Chloroquine or hydroxychloroquine. Int J Antimicrob Agents 2020; 55(4): 105945.
[] [PMID: 32194152]
Mitjà O, Clotet B. Use of antiviral drugs to reduce COVID-19 transmission. Lancet Glob Health 2020; 8(5): e639-40.
[] [PMID: 32199468]
Rathi S, Ish P, Kalantri A, Kalantri S. Hydroxychloroquine prophylaxis for COVID-19 contacts in India. Lancet Infect Dis 2020; 20(10): 1118-9.
[] [PMID: 32311324]
Principi N, Esposito S. Chloroquine or hydroxychloroquine for prophylaxis of COVID-19. Lancet Infect Dis 2020; 20(10): 1118.
[] [PMID: 32311322]
Multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia, 2020,[Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 2020; 43(3): 185-188..
Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care 2020; 57: 279-83.
[] [PMID: 32173110]
CHEN J, LIU D, LIU L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Uni (Med Sci) 2020; 49(1): 0-0.
Zhou D, Dai SM, Tong Q. COVID-19: A recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother, dkaa114 2020.
Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents 2020; 55(4): 105932.
[] [PMID: 32145363]
Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: What to expect for covid-19? Int J Antimicrob Agents 2020; 55(5): 105938.
[] [PMID: 32171740]
Pacheco RL, Riera R. Hydroxychloroquine and chloroquine for COVID-19 infection. Rapid systematic review. J Evid Based Healthc 2020; 2(1)
Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; 56(1): 105949.
[] [PMID: 32205204]
Nicastri E, Petrosillo N, Ascoli Bartoli T, et al. National Institute for the Infectious Diseases “L. Spallanzani”, IRCCS. Recommendations for COVID-19 clinical management. Infect Dis Rep 2020; 12(1): 8543.
[] [PMID: 32218915]
Gautret P, Lagier JC, Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel medicine and infectious disease 2020; 50(4): 384.
Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect 2020; 50(4): 384.
[] [PMID: 32240719]
García PJ. Corruption in global health: The open secret. Lancet 2019; 394(10214): 2119-24.
[] [PMID: 31785827]
Herper M. Novartis steps up to study of hydroxychloroquine in covid-19. 2020. Available from: novartis-study-hydroxychloroquine/
Hempelmann E. Hemozoin biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors. Parasitol Res 2007; 100(4): 671-6.
[] [PMID: 17111179]
Pelt J, Busatto S, Ferrari M, Thompson EA, Mody K, Wolfram J. Chloroquine and nanoparticle drug delivery: A promising combination. Pharmacol Ther 2018; 191: 43-9.
[] [PMID: 29932886]
Wolfram J, Nizzero S, Liu H, et al. A chloroquine-induced macrophage-preconditioning strategy for improved nanodelivery. Sci Rep 2017; 7(1): 13738.
[] [PMID: 29062065]
Miller SE, Mathiasen S, Bright NA, et al. CALM regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature. Dev Cell 2015; 33(2): 163-75.
[] [PMID: 25898166]
Gentile E, Cilurzo F, Di Marzio L, et al. Liposomal chemotherapeutics. Future Oncol 2013; 9(12): 1849-59.
[] [PMID: 24295415]
Wu K, Li W, Peng G, Li F. Crystal structure of NL63 respiratory coronavirus receptor-binding domain complexed with its human receptor. Proc Natl Acad Sci USA 2009; 106(47): 19970-4.
[] [PMID: 19901337]
Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426(6965): 450-4.
[] [PMID: 14647384]
Wang H, Yang P, Liu K, et al. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res 2008; 18(2): 290-301.
[] [PMID: 18227861]
Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367(6483): 1260-3.
[] [PMID: 32075877]
Dowall SD, Bosworth A, Watson R, et al. Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model. J Gen Virol 2015; 96(12): 3484-92.
[] [PMID: 26459826]
Madrid PB, Chopra S, Manger ID, et al. A systematic screen of FDA-approved drugs for inhibitors of biological threat agents. PLoS One 2013; 8(4): e60579.
[] [PMID: 23577127]
Shang J, Wan Y, Luo C, et al. Cell entry mechanisms of SARS-CoV-2. Proceedings of the National Academy of Sciences. 117(21): 11727-34.
Roques P, Thiberville SD, Dupuis-Maguiraga L, et al. Paradoxical effect of chloroquine treatment in enhancing chikungunya virus infection. Viruses 2018; 10(5): 268.
[] [PMID: 29772762]
de Jonge N, Peckys DB, Kremers GJ, Piston DW. Electron microscopy of whole cells in liquid with nanometer resolution. Proc Natl Acad Sci USA 2009; 106(7): 2159-64.
[] [PMID: 19164524]
Richert-Pöggeler KR, Franzke K, Hipp K, Kleespies RG. Electron microscopy methods for virus diagnosis and high resolution analysis of viruses. Front Microbiol 2019; 9: 3255.
[] [PMID: 30666247]
Pan Y, Wang S, Shan Y, et al. Ultrafast tracking of a single live virion during the invagination of a cell membrane. Small 2015; 11(23): 2782-8.
[] [PMID: 25689837]
Herrmann A, Sieben C. Single-virus force spectroscopy unravels molecular details of virus infection. Integr Biol 2015; 7(6): 620-32.
[] [PMID: 25923471]
Kamiyama D, Sekine S, Barsi-Rhyne B, et al. Versatile protein tagging in cells with split fluorescent protein. Nat Commun 2016; 7(1): 11046.
[] [PMID: 26988139]
Wang IH, Burckhardt CJ, Yakimovich A, Greber UF. Imaging, tracking and computational analyses of virus entry and egress with the cytoskeleton. Viruses 2018; 10(4): 166.
[] [PMID: 29614729]
Rust MJ, Bates M, Zhuang X. Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nat Methods 2006; 3(10): 793-5.
[] [PMID: 16896339]
Betzig E, Patterson GH, Sougrat R, et al. Imaging intracellular fluorescent proteins at nanometer resolution. Science 2006; 313(5793): 1642-5.
[] [PMID: 16902090]
Hell SW, Wichmann J. Breaking the diffraction resolution limit by stimulated emission: Stimulated-emission-depletion fluorescence microscopy. Opt Lett 1994; 19(11): 780-2.
[] [PMID: 19844443]
Willig KI, Kellner RR, Medda R, Hein B, Jakobs S, Hell SW. Nanoscale resolution in GFP-based microscopy. Nat Methods 2006; 3(9): 721-3.
[] [PMID: 16896340]
Manley S, Gillette JM, Patterson GH, et al. High-density mapping of single-molecule trajectories with photoactivated localization microscopy. Nat Methods 2008; 5(2): 155-7.
[] [PMID: 18193054]
Kim D, Deerinck TJ, Sigal YM, Babcock HP, Ellisman MH, Zhuang X. Correlative stochastic optical reconstruction microscopy and electron microscopy. PLoS One 2015; 10(4): e0124581.
[] [PMID: 25874453]
Jin C, Che B, Guo Z, et al. Single virus tracking of Ebola virus entry through lipid rafts in living host cells. Biosafety and health 2020; 2: 25-31.
c19study. Global HCQ studies. 2020. Available from:

© 2024 Bentham Science Publishers | Privacy Policy