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].
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 (http://www.chictr.org.cn) 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.
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.
References
- Wang, M. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 30, 269–271 (2020).
- Holshue, M. L. et al. First case of 2019 novel coronavirus in the United States. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2001191 (2020).
- Weniger, H. Review of side effects and toxicity of chloroquine. Bull. World Health 79, 906 (1979).
- McChesney, E. W. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am. J. Med. 75, 11–18 (1983).
- Mauthe, M. et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy 14, 1435–1455 (2018).
- Savarino, A. et al. New insights into the antiviral effects of chloroquine. Lancet Infect. Dis. 6, 67–69 (2006).
- Mingo, R. M. et al. Ebola virus and severe acute respiratory syndrome coronavirus display late cell entry kinetics: evidence that transport to NPC1+ endolysosomes is a rate-defining step. J. Virol. 89, 2931–2943 (2015).
- Zheng, N., Zhang, X. & Rosania, G. R. Effect of phospholipidosis on the cellular pharmacokinetics of chloroquine. J. Pharmacol. Exp. Ther. 336, 661–671 (2011).
- Ohkuma, S. & Poole, B. Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc. Natl Acad. Sci. USA 75, 3327–3331 (1978).
- Popert, A. J. Choloroquine: a review. Rheumatology 15, 235–238 (1976).
- Laaksonen, A. L., Koskiahde, V. & Juva, K. Dosage of antimalarial drugs for children with juvenile rheumatoid arthritis and systemic lupus erythematosus. A clinical study with determination of serum concentrations of chloroquine and hydroxychloroquine. Scand. J. rheumatol. 3, 103–108 (1974).
- Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020).
[21] J.M. Rolain, P. Colson, D. RaoultRecycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century – Int J Antimicrob Agents, 30 (2007), pp. 297-308, 10.1016/j.ijantimicag.2007.05.015
ArticleDownload PDFView Record in ScopusGoogle Scholar
[22] E. Bosseboeuf, M. Aubry, T. Nhan, J.J. de Pina, J.M. Rolain, D. Raoult, et al.Azithromycin inhibits the replication of Zika virus – J Antivir Antiretrovir, 10 (2018), pp. 6-11, 10.4172/1948-5964.1000173
View Record in ScopusGoogle Scholar
[23] M. Wang, R. Cao, L. Zhang, X. Yang, J. Liu, M. Xu, et al.Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro – Cell Res (2020 Feb 4), 10.1038/s41422-020-0282-0
[24] J. Gao, Z. Tian, X. YangBreakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies – Biosci Trends (2020 Feb 19), 10.5582/bst.2020.01047
[26] 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 PneumoniaExpert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia [in Chinese] – Zhonghua Jie He He Hu Xi Za Zhi, 43 (2020), p. E019, 10.3760/cma.j.issn.1001-0939.2020.0019
[27] M.A. Al-BariChloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases – J Antimicrob Chemother, 70 (2015), pp. 1608-1621, 10.1093/jac/dkv018
View Record in Scopus – Google Scholar
[28] D. Raoult, M. Drancourt, G. VestrisBactericidal effect of doxycycline associated with lysosomotropic agents on Coxiella burnetii in P388D1 cells – Antimicrob Agents Chemother, 34 (1990), pp. 1512-1514, 10.1128/aac.34.8.1512
CrossRef View Record in Scopus Google Scholar
[29] D. Raoult, P. Houpikian, H. Tissot Dupont, J.M. Riss, J. Arditi-Djiane, P. BrouquiTreatment of Q fever endocarditis: comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine – Arch Intern Med, 159 (1999), pp. 167-173, 10.1001/archinte.159.2.167
View Record in ScopusGoogle Scholar
[30] A. Boulos, J.M. Rolain, D. RaoultAntibiotic susceptibility of Tropheryma whipplei in MRC5 cells – Antimicrob Agents Chemother, 48 (2004), pp. 747-752, 10.1128/aac.48.3.747-752.2004
View Record in ScopusGoogle Scholar
[31] F. Fenollar, X. Puéchal, D. RaoultWhipple’s disease – N Engl J Med, 356 (2007), pp. 55-66, 10.1056/NEJMra062477
View Record in ScopusGoogle Scholar
[32] E. Keyaerts, L. Vijgen, P. Maes, J. Neyts, M. Van RanstIn vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine – Biochem Biophys Res Commun, 323 (2004), pp. 264-268, 10.1016/j.bbrc.2004.08.085
ArticleDownload PDFView Record in ScopusGoogle Scholar
[33] A. Savarino, L. Di Trani, I. Donatelli, R. Cauda, A. CassoneNew insights into the antiviral effects of chloroquine – Lancet Infect Dis, 6 (2006), pp. 67-69, 10.1016/S1473-3099(06)70361-9
ArticleDownload PDFView Record in ScopusGoogle Scholar
[34] P. Colson, J.M. Rolain, D. RaoultChloroquine for the 2019 novel coronavirus SARS-CoV-2 – Int J Antimicrob Agents (2020), Article 105923, 10.1016/j.ijantimicag.2020.105923
ArticleDownload PDFGoogle Scholar
[35] J.C. Lagier, F. Fenollar, H. Lepidi, R. Giorgi, M. Million, D. RaoultTreatment of classic Whipple’s disease: from in vitro results to clinical outcome – J Antimicrob Chemother, 69 (2014), pp. 219-227, 10.1093/jac/dkt310
CrossRefView Record in ScopusGoogle Scholar
[36] M.J. Vincent, E. Bergeron, S. Benjannet, B.R. Erickson, P.E. Rollin, T.G. Ksiazek, et al.Chloroquine is a potent inhibitor of SARS coronavirus infection and spread – Virol J, 2 (2005), p. 69, 10.1186/1743-422X-2-69
[37] D.L. Barnard, C.W. Day, K. Bailey, M. Heiner, R. Montgomery, L. Lauridsen, et al.Evaluation of immunomodulators, interferons and known in vitro SARS-coV inhibitors for inhibition of SARS-coV replication in BALB/c mice – Antivir Chem Chemother, 17 (2006), pp. 275-284, 10.1177/095632020601700505
CrossRefView Record in ScopusGoogle Scholar
[38] C. Biot, W. Daher, N. Chavain, T. Fandeur, J. Khalife, D. Dive, et al.Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities – J Med Chem, 49 (2006), pp. 2845-2849, 10.1021/jm0601856
CrossRefView Record in ScopusGoogle Scholar
[39] M. Kono, K. Tatsumi, A.M. Imai, K. Saito, T. Kuriyama, H. ShirasawaInhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK – Antiviral Res, 77 (2008), pp. 150-152, 10.1016/j.antiviral.2007.10.011
ArticleDownload PDFView Record in ScopusGoogle Scholar
[40] E. Keyaerts, S. Li, L. Vijgen, E. Rysman, J. Verbeeck, M. Van Ranst, et al.Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice – Antimicrob Agents Chemother, 53 (2009), pp. 3416-3421, 10.1128/AAC.01509-08
CrossRefView Record in ScopusGoogle Scholar
[41] T. Takano, Y. Katoh, T. Doki, T. HohdatsuEffect of chloroquine on feline infectious peritonitis virus infection in vitro and in vivo – Antiviral Res, 99 (2013), pp. 100-107, 10.1016/j.antiviral.2013.04.016
Article Download PDF View Record in Scopus Google Scholar
[42] A.H. de Wilde, D. Jochmans, C.C. Posthuma, J.C. Zevenhoven-Dobbe, S. van Nieuwkoop, T.M. Bestebroer, et al.Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture – Antimicrob Agents Chemother, 58 (2014), pp. 4875-4884, 10.1128/AAC.03011-14
View Record in ScopusGoogle Scholar
[50] Chattopadhyay R, Mahajan B, Kumar S (2007) Assessment of safety of the major antimalarial drugs. Expert Opin Drug Saf 6:505–521
[51] García-Serradilla M, Risco C, Pacheco B (2019) Drug repurposing for new, efficient, broad spectrum antivirals. Virus Res 264:22–31
[52] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. https://doi.org/10.1016/S0140-6736(20)30183-5
Article – PubMed – Google Scholar
[53] Lo MK, Jordan R, Arvey A, Sudhamsu J, Shrivastava-Ranjan P, Hotard AL, Flint M, McMullan LK, Siegel D, Clarke MO, Mackman RL, Hui HC, Perron M, Ray AS, Cihlar T, Nichol ST, Spiropoulou CF (2017) GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci Rep 7:43395
[54] National Health Commission of the People’s Republic of China (2020) http://www.nhc.gov.cn/xcs/yqfkdt/202001/e71bd2e7a0824ca69f87bbf1bef2a3c9.shtml
Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF (2015) Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology 23:231–269
[55] Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R (2003) Effects of chloroquine on viral infections: an old drug against today’s diseases. Lancet Infect Dis 3(11):722–727
[56] Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, Bannister R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel D, Ray AS, Cihlar T, Jordan R, Denison MR, Baric RS (2017) Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Trans Med. https://doi.org/10.1126/scitranslmed.aal3653
[57] Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi ZL, Hu Z, Zhong W, Xiao G (2020) Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. https://doi.org/10.1038/s41422-020-0282-0
Article – PubMed – Google Scholar
[58] Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC et al (2016) Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531:381–385
[59] World Health Organization (WHO) (2020a) https://www.who.int/csr/sars/en/. Accessed 29 Jan 2020
[60] World Health Organization (WHO) (2020b) https://www.who.int/emergencies/mers-cov/en/. Accessed 29 Jan 2020
[61] World Health Organization (WHO) (2020c) https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200129-sitrep-9-ncov-v2.pdf?sfvrsn=e2c8915_2. Accessed 29 Jan 2020
[62] Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W (2020) China Novel Coronavirus Investigating and Research Team (2020) A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. https://doi.org/10.1056/NEJMoa2001017
