Chloroquine and hydroxychloroquine : new weapon available to fight COVID-19


Chloroquine and hydroxychloroquine are drugs derived from the quinoline molecule.

Both are used as antimalarial blood schizonticides, and hydroxychloroquine is also frequently used as an antirheumatic.

Their mechanism of action is not entirely understood. However, despite their varying therapeutic dosage and toxicity, both drugs have similar clinical indications and side effects.

The latest studies show that two drugs, remdesivir (GS-5734) and chloroquine (CQ) phosphate, efficiently inhibited SARS-CoV-2 infection in vitro1.

The respiratory disease caused by the new coronavirus (SARS-CoV-2) that emerged in December 2019 in China gave a big impulse to research centers to test new or old molecules, they can respond effectively to the care of COVID-19.

Indeed, following the very recent publication of results showing the in vitro activity of chloroquine against SARS-CoV-2 [23], data have been reported on the efficacy of this drug in patients with SARS-CoV-2-related pneumonia (named COVID-19) at different levels of severity [24,25].

Thus, following the in vitro results, 20 clinical studies were launched in several Chinese hospitals.

The first results obtained from more than 100 patients showed the superiority of chloroquine compared with treatment of the control group in terms of reduction of exacerbation of pneumonia, duration of symptoms and delay of viral clearance, all in the absence of severe side effects [24,25].

This has led in China to 7include chloroquine in the recommendations regarding the prevention and treatment of COVID-19 pneumonia [24,26].

There is a strong rationality for the use of chloroquine to treat infections with intracellular micro-organisms.

Thus, malaria has been treated for several decades with this molecule [27]. In addition, our team has used hydroxychloroquine for the first time for intracellular bacterial infections since 30 years to treat the intracellular bacterium Coxiella burnetii, the agent of Q fever, for which we have shown in vitro and then in patients that this compound is the only one efficient for killing these intracellular pathogens [28,29].

Since then, we have also shown the activity of hydroxychloroquine on Tropheryma whipplei, the agent of Whipple’s disease, which is another intracellular bacterium for which hydroxychloroquine has become a reference drug [30,31].

Altogether, one of us (DR) has treated ~4000 cases of C. burnetii or T. whipplei infections over 30 years (personal data).

Regarding viruses, for reasons probably partly identical involving alkalinisation by chloroquine of the phagolysosome, several studies have shown the effectiveness of this molecule, including against coronaviruses among which is the severe acute respiratory syndrome (SARS)-associated coronavirus [21,32,33] (Table 1).

We previously emphasised interest in chloroquine for the treatment of viral infections in this journal [21], predicting its use in viral infections lacking drugs. Following the discovery in China of the in vitro activity of chloroquine against SARS-CoV-2, discovered during culture tests on Vero E6 cells with 50% and 90% effective concentrations (EC50 and EC90 values) of 1.13 μM and 6.90 μM, respectively (antiviral activity being observed when addition of this drug was carried out before or after viral infection of the cells) [23], we awaited with great interest the clinical data [34].

The subsequent in vivo data were communicated following the first results of clinical trials by Chinese teams [24] and also aroused great enthusiasm among us.

They showed that chloroquine could reduce the length of hospital stay and improve the evolution of COVID-19 pneumonia [24,26], leading to recommend the administration of 500 mg of chloroquine twice a day in patients with mild, moderate and severe forms of COVID-19 pneumonia.

At such a dosage, a therapeutic concentration of chloroquine might be reached. With our experience on 2000 dosages of hydroxychloroquine during the past 5 years in patients with long-term treatment (>1 year), we know that with a dosage of 600 mg/day we reach a concentration of 1 μg/mL [35].

The optimal dosage for SARS-CoV-2 is an issue that will need to be assessed in the coming days. For us, the activity of hydroxychloroquine on viruses is probably the same as that of chloroquine since the mechanism of action of these two molecules is identical, and we are used to prescribe for long periods hydroxychloroquine, which would be therefore our first choice in the treatment of SARS-CoV-2. For optimal treatment, it may be necessary to administer a loading dose followed by a maintenance dose.

Table 1. Main results of studies on the activity of chloroquine or hydroxychloroquine on coronavirusesa

Reference Compound(s) Targeted virus System used for antiviral activity screening Antiviral effect
[32] Chloroquine SARS-CoV Vero (African green monkey kidney) E6 cells EC50 = 8.8 ± 1.2 μM
[36] Chloroquine Vero E6 cells EC50 = 4.4 ± 1.0 μM
[37] Chloroquine, chloroquine monophosphate, chloroquine diphosphate SARS-CoV (four strains) Vero 76 cells Chloroquine: EC50 = 1–4 μM
Chloroquine monophosphate: EC50 = 4–6 μM
Chloroquine diphosphate: EC50 = 3–4 μM
BALB/c mice Intraperitoneal or intranasal chloroquine administration, beginning 4 h prior to virus exposure: 50 mg/kg but not 10 mg/kg or 1 mg/kg reduced for the intranasal route (but not the intraperitoneal route) viral lung titres from mean ± S.D. of 5.4 ± 0.5 to 4.4 ± 1.2 in log10 CCID50/g at Day 3 (considered as not significant)
[38] Chloroquine, hydroxychloroquine SARS-CoV Vero cells Chloroquine: EC50 = 6.5 ± 3.2 μM
Hydroxychloroquine: EC50 = 34 ± 5 μM
Feline coronavirus Crandell–Reese feline kidney (CRFK) cells Chloroquine: EC50 > 0.8 μM
Hydroxychloroquine: EC50 = 28 ± 27 μM
[39] Chloroquine HCoV-229E Human epithelial lung cells (L132) Chloroquine at concentrations of 10 μM and 25 μM inhibited HCoV-229E release into the culture supernatant
[40] Chloroquine HCoV-OC43 HRT-18 cells EC50 = 0.306 ± 0.0091 μM
Newborn C57BL/6 mice; chloroquine administration transplacentally and via maternal milk 100%, 93%, 33% and 0% survival rate of pups when mother mice were treated per day with 15, 5, 1 and 0 mg/kg body weight, respectively
[41] Chloroquine Feline infectious peritonitis virus (FIPV) Felis catus whole fetus-4 cells FIPV replication was inhibited in a chloroquine concentration-dependent manner
[42] Chloroquine SARS-CoV Vero E6 cells EC50 = 4.1 ± 1.0 μM
MERS-CoV Huh7 cells (human liver cell line) EC50 = 3.0 ± 1.1 μM
HCoV-229E-GFP (GFP-expressing recombinant HCoV-229E) Huh7 cells (human liver cell line) EC50 = 3.3 ± 1.2 μM
[23] Chloroquine SARS-CoV-2 Vero E6 cells EC50 = 1.13 μM

CCID50, 50% cell culture infectious dose; CoV, coronavirus; EC50, 50% effective concentration (mean ± S.D.); GFP, green fluorescent protein; HCoV, human coronavirus; MERS, Middle East respiratory syndrome; SARS, severe acute respiratory syndrome; S.D., standard deviation.

See also [21] (Table 1) for additional references.

Remdesivir is a nucleoside analog prodrug developed by Gilead Sciences (USA).

A recent case report showed that treatment with remdesivir improved the clinical condition of the first patient infected by SARS-CoV-2 in the United States2, and a phase III clinical trial of remdesivir against SARS-CoV-2 was launched in Wuhan on February 4, 2020.

However, as an experimental drug, remdesivir is not expected to be largely available for treating a very large number of patients in a timely manner.

Therefore, of the two potential drugs, CQ appears to be the drug of choice for large-scale use due to its availability, proven safety record, and a relatively low cost.

In light of the preliminary clinical data, CQ has been added to the list of trial drugs in the Guidelines for the Diagnosis and Treatment of COVID-19 (sixth edition) published by National Health Commission of the People’s Republic of China.

CQ (N4-(7-Chloro-4-quinolinyl)-N1,N1-diethyl-1,4-pentanediamine) has long been used to treat malaria and amebiasis.

However, Plasmodium falciparum developed widespread resistance to it, and with the development of new antimalarials, it has become a choice for the prophylaxis of malaria. In addition, an overdose of CQ can cause acute poisoning and death3.

In the past years, due to infrequent utilization of CQ in clinical practice, its production and market supply was greatly reduced, at least in China. Hydroxychloroquine (HCQ) sulfate, a derivative of CQ, was first synthesized in 1946 by introducing a hydroxyl group into CQ and was demonstrated to be much less (~40%) toxic than CQ in animals4.

More importantly, HCQ is still widely available to treat autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

Since CQ and HCQ share similar chemical structures and mechanisms of acting as a weak base and immunomodulator, it is easy to conjure up the idea that HCQ may be a potent candidate to treat infection by SARS-CoV-2.

Actually, as of February 23, 2020, seven clinical trial registries were found in Chinese Clinical Trial Registry ( for using HCQ to treat COVID-19.

Whether HCQ is as efficacious as CQ in treating SARS-CoV-2 infection still lacks the experimental evidence.

To this end, we evaluated the antiviral effect of HCQ against SARS-CoV-2 infection in comparison to CQ in vitro. First, the cytotoxicity of HCQ and CQ in African green monkey kidney VeroE6 cells (ATCC-1586) was measured by standard CCK8 assay, and the result showed that the 50% cytotoxic concentration (CC50) values of CQ and HCQ were 273.20 and 249.50 μM, respectively, which are not significantly different from each other (Fig. 1a).

To better compare the antiviral activity of CQ versus HCQ, the dose–response curves of the two compounds against SARS-CoV-2 were determined at four different multiplicities of infection (MOIs) by quantification of viral RNA copy numbers in the cell supernatant at 48 h post infection (p.i.).

The data summarized in Fig. 1a and Supplementary Table S1 show that, at all MOIs (0.01, 0.02, 0.2, and 0.8), the 50% maximal effective concentration (EC50) for CQ (2.71, 3.81, 7.14, and 7.36 μM) was lower than that of HCQ (4.51, 4.06, 17.31, and 12.96 μM). The differences in EC50 values were statistically significant at an MOI of 0.01 (P < 0.05) and MOI of 0.2 (P < 0.001) (Supplementary Table S1).

It is worth noting that the EC50 values of CQ seemed to be a little higher than that in our previous report (1.13 μM at an MOI of 0.05)1, which is likely due to the adaptation of the virus in cell culture that significantly increased viral infectivity upon continuous passaging. Consequently, the selectivity index (SI = CC50/EC50) of CQ (100.81, 71.71, 38.26, and 37.12) was higher than that of HCQ (55.32, 61.45, 14.41, 19.25) at MOIs of 0.01, 0.02, 0.2, and 0.8, respectively.

These results were corroborated by immunofluorescence microscopy as evidenced by different expression levels of virus nucleoprotein (NP) at the indicated drug concentrations at 48 h p.i. (Supplementary Fig. S1).

Taken together, the data suggest that the anti-SARS-CoV-2 activity of HCQ seems to be less potent compared to CQ, at least at certain MOIs.

Fig. 1a: Comparative antiviral efficacy and mechanism of action of CQ and HCQ against SARS-CoV-2 infection in vitro.

Cytotoxicity and antiviral activities of CQ and HCQ. The cytotoxicity of the two drugs in Vero E6 cells was determined by CCK-8 assays. Vero E6 cells were treated with different doses of either compound or with PBS in the controls for 1 h and then infected with SARS-CoV-2 at MOIs of 0.01, 0.02, 0.2, and 0.8. The virus yield in the cell supernatant was quantified by qRT-PCR at 48 h p.i. Y-axis represents the mean of percent inhibition normalized to the PBS group. The experiments were repeated twice. bc Mechanism of CQ and HCQ in inhibiting virus entry. Vero E6 cells were treated with CQ or HCQ (50 μM) for 1 h, followed by virus binding (MOI = 10) at 4 °C for 1 h. Then the unbound virions were removed, and the cells were further supplemented with fresh drug-containing medium at 37 °C for 90 min before being fixed and stained with IFA using anti-NP antibody for virions (red) and antibodies against EEA1 for EEs (green) or LAMP1 for ELs (green). The nuclei (blue) were stained with Hoechst dye. The portion of virions that co-localized with EEs or ELs in each group (n > 30 cells) was quantified and is shown in b. Representative confocal microscopic images of viral particles (red), EEA1+ EEs (green), or LAMP1+ ELs (green) in each group are displayed in c. The enlarged images in the boxes indicate a single vesicle-containing virion. The arrows indicated the abnormally enlarged vesicles. Bars, 5 μm. Statistical analysis was performed using a one-way analysis of variance (ANOVA) with GraphPad Prism (F = 102.8, df = 5,182, ***P < 0.001).

Both CQ and HCQ are weak bases that are known to elevate the pH of acidic intracellular organelles, such as endosomes/lysosomes, essential for membrane fusion5. In addition, CQ could inhibit SARS-CoV entry through changing the glycosylation of ACE2 receptor and spike protein6.

Time-of-addition experiment confirmed that HCQ effectively inhibited the entry step, as well as the post-entry stages of SARS-CoV-2, which was also found upon CQ treatment (Supplementary Fig. S2).

To further explore the detailed mechanism of action of CQ and HCQ in inhibiting virus entry, co-localization of virions with early endosomes (EEs) or endolysosomes (ELs) was analyzed by immunofluorescence analysis (IFA) and confocal microscopy.

Quantification analysis showed that, at 90 min p.i. in untreated cells, 16.2% of internalized virions (anti-NP, red) were observed in early endosome antigen 1 (EEA1)-positive EEs (green), while more virions (34.3%) were transported into the late endosomal–lysosomal protein LAMP1+ ELs (green) (n > 30 cells for each group).

By contrast, in the presence of CQ or HCQ, significantly more virions (35.3% for CQ and 29.2% for HCQ; P < 0.001) were detected in the EEs, while only very few virions (2.4% for CQ and 0.03% for HCQ; P < 0.001) were found to be co-localized with LAMP1+ ELs (n > 30 cells) (Fig. 1b, c).

This suggested that both CQ and HCQ blocked the transport of SARS-CoV-2 from EEs to ELs, which appears to be a requirement to release the viral genome as in the case of SARS-CoV7.

Interestingly, we found that CQ and HCQ treatment caused noticeable changes in the number and size/morphology of EEs and ELs (Fig. 1c).

In the untreated cells, most EEs were much smaller than ELs (Fig. 1c). In CQ- and HCQ-treated cells, abnormally enlarged EE vesicles were observed (Fig. 1c, arrows in the upper panels), many of which are even larger than ELs in the untreated cells.

This is in agreement with previous report that treatment with CQ induced the formation of expanded cytoplasmic vesicles8.

Within the EE vesicles, virions (red) were localized around the membrane (green) of the vesicle. CQ treatment did not cause obvious changes in the number and size of ELs; however, the regular vesicle structure seemed to be disrupted, at least partially.

By contrast, in HCQ-treated cells, the size and number of ELs increased significantly (Fig. 1c, arrows in the lower panels).

Since acidification is crucial for endosome maturation and function, we surmise that endosome maturation might be blocked at intermediate stages of endocytosis, resulting in failure of further transport of virions to the ultimate releasing site.

CQ was reported to elevate the pH of lysosome from about 4.5 to 6.5 at 100 μM9. To our knowledge, there is a lack of studies on the impact of HCQ on the morphology and pH values of endosomes/lysosomes. Our observations suggested that the mode of actions of CQ and HCQ appear to be distinct in certain aspects.

It has been reported that oral absorption of CQ and HCQ in humans is very efficient. In animals, both drugs share similar tissue distribution patterns, with high concentrations in the liver, spleen, kidney, and lung reaching levels of 200–700 times higher than those in the plasma10.

It was reported that safe dosage (6–6.5 mg/kg per day) of HCQ sulfate could generate serum levels of 1.4–1.5 μM in humans11. Therefore, with a safe dosage, HCQ concentration in the above tissues is likely to be achieved to inhibit SARS-CoV-2 infection.

Clinical investigation found that high concentration of cytokines were detected in the plasma of critically ill patients infected with SARS-CoV-2, suggesting that cytokine storm was associated with disease severity12.

Other than its direct antiviral activity, HCQ is a safe and successful anti-inflammatory agent that has been used extensively in autoimmune diseases and can significantly decrease the production of cytokines and, in particular, pro-inflammatory factors.

Therefore, in COVID-19 patients, HCQ may also contribute to attenuating the inflammatory response. In conclusion, our results show that HCQ can efficiently inhibit SARS-CoV-2 infection in vitro. In combination with its anti-inflammatory function, we predict that the drug has a good potential to combat the disease.

This possibility awaits confirmation by clinical trials. We need to point out, although HCQ is less toxic than CQ, prolonged and overdose usage can still cause poisoning. And the relatively low SI of HCQ requires careful designing and conducting of clinical trials to achieve efficient and safe control of the SARS-CoV-2 infection.

In a very recent work by a research team led by Drs. Gengfu Xiao, Wu Zhong and Zhihong Hu, the antiviral efficiency of the FDA-approved drugs including ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine (CQ) and two well-known broad-spectrum antiviral drugs remdesivir (RDV, GS-5734) and favipiravir (T-705) were evaluated against a clinical isolate of 2019-nCoV in a cell culture infection model (Wang et al.2020 [57]).

The authors found that two compounds CQ (EC50 value = 1.13 μmol/L; CC50 > 100 μmol/L, SI > 88.50) and RDV (EC50 = 0.77 μmol/L; CC50 > 100 μmol/L; SI > 129.87) potently blocked virus infection at low-micromolar concentration and showed high selectivity index (SI).

From the in vitro results, these two compounds appear promising to be transformed into clinical drugs for treatment of 2019-nCoV infections.

RDV is an adenosine analogue prodrug and can be incorporated into nascent chains of viral RNA, resulting in pre-mature termination of RNA synthesis. RDV has been shown to possess a potent and broad-spectrum antiviral activity against a diverse panel of RNA viruses such as SARS-CoV, MERS-CoV, Ebola virus (EBOV), Marburg virus, Nipah virus, Hendra virus, and respiratory syncytial virus in cell culture and mouse infection models (Warren et al.2016 [58] ; Sheahan et al.2017 [56] ; Lo et al.2017 [53] ).

Currently, it is in clinical trials to evaluate its efficacy against Ebola virus infections. The study by Wang et al. (2020 [57] ) extends its antiviral activity to the new deadly coronavirus 2019-nCoV. However, RDV has not been used in any clinical treatment, and the clinical effectiveness and safety needs to be further investigated.

Remarkably, CQ was identified as a potent inhibitor against 2019-nCoV in cell culture infection model (Wang et al.2020 [57] ).

CQ, a weak base 4-aminoquinolone derivative, has been used as a standard antimalarial drug for more than half a century for its rapid schizonticidal activity against all malarial parasite infections.

CQ also has anti-inflammatory properties and has been approved for the clinical treatment of autoimmune diseases such as lupus erythematosus and rheumatoid arthritis (Rainsford et al.2015 [54] ).

Recently, CQ has been proven to have a broad-spectrum antiviral activity against a panel of viruses, including SARS-CoV, MERS-CoV, EBOV, influenza A virus, Chikungunya virus, human immunodeficiency virus, dengue virus, West Nile virus, Crimean Congo hemorrhagic fever virus, and hepatitis A virus (García-Serradilla et al.2019 [51] ).

It is not surprising that CQ can suppress the infection of a diverse group of viruses.

CQ can efficiently enter the cells and accumulate in acidic compartments like lysosomes, endosomes and trans-Golgi network vesicles, consequently raising their pH value while many viruses need the acidic endocytic organelles at some stages of their replication, such as viral uncoating and cellular entry via membrane fusion.

CQ is also able to impair the maturation of viral proteins and post-translational modification viral receptors like ACE2 for SARS-CoV by inhibition of pH-dependent enzymes such as proteases or glycosyltransferases (Savarino et al.2003 [55] ).

In view of its antiviral activity to SARS-CoV and MERS-CoV, it is not unexpected that CQ possesses an antiviral activity against 2019-nCoV. However, this finding is clinically important and timely as the 2019-nCoV is currently spreading rapidly in China and causing severe respiratory diseases and deaths of many patients.

As CQ is the first-line drug for the treatment of malaria and other illnesses with a proven safe record for several decades, it most likely represents the best candidate to be applied and evaluated immediately in the clinical treatment of acute 2019-nCoV infections.

For benefits of 2019-nCoV patients, it is suggested that the potential clinical use of CQ be exploited and its efficacy evaluated during the 2019-nCoV epidemics. All the repurposed uses of CQ in the treatment of viral diseases should comply with the regulations of the administrative authorities and medical ethics.

Although CQ belongs to the safest antimalarial drugs ever discovered, adverse effects of CQ alone or in combination with other drugs were also observed among some patients, who showed mild symptoms such as dizziness, nausea and diarrhoea (Chattopadhyay et al.2007 [50] ).

In rare occasions, long-term use of CQ may be associated with neuromyopathy and retinopathy (Chattopadhyay et al.2007 [50] ). CQ is considered safe for use during pregnancy, but its administration is contraindicated in patients with known hypersensitivity, severe renal and hepatic diseases, a history of epilepsy, and psoriasis.

Therefore, when used in the control of viral diseases, contraindication of CQ should be taken into account by evaluation of the physical condition, underlying diseases and comorbidities of the patients.

It is hoped that CQ and many other approved clinical drugs can be repurposed to the antiviral treatment of emerging viral diseases that do have other effective antiviral treatment.


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