Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Vincent, Martin J.; Bergeron, Éric; Benjannet, Suzanne; Erickson, Bobbie R.; Rollin, Pierre E.; Ksiazek, Thomas G.; Seidah, Nabil G.; Nichol, Stuart T.

doi:10.1186/1743-422x-2-69

Cited by 1,607 publications

(1,194 citation statements)

References 26 publications

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“…When added extracellularly, chloroquine enters in acidic, low pH organelles, such as endosomes, Golgi vesicles, and lysosomes where it is protonated and concentrated. Chloroquine can affect virus entry in many ways, inhibiting pH-dependent fusion of viral particles or altering the glycosylation of cellular receptors (38). We showed that pretreated cells are resistant to infection by CHIKV, suggesting that chloroquine essentially affects either the pH-dependent fusion or the complex glycosylation of a cellular receptor.…”

Section: Discussionmentioning

confidence: 89%

“…The presence of a critical His at the cleavage site of PCs was also reported in other substrates such as integrin-␣4 (36), where it was shown to impart a pH dependence on cleavage (36 -38). Indeed, this observation led us originally to propose that alkalinizing agents such as NH 4 Cl and chloroquine may affect the processing of SARS-CoV S-glycoprotein (38). Using the same reasoning, we tested the effect of preincubating the cells with 10 M chloroquine on the ability of furin to process the E3E2 proprotein from 05.115 CHIKV isolate (Fig.…”

Section: Furin-like Convertases and The Processing Of E3e2mentioning

confidence: 99%

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Inhibition of Chikungunya Virus Infection in Cultured Human Muscle Cells by Furin Inhibitors

Ozden¹,

Lucas‐Hourani

Ceccaldi³

et al. 2008

Journal of Biological Chemistry

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120

132

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Chikungunya virus (CHIKV) is a mosquito-transmittedAlphavirus that causes in humans an acute infection characterized by polyarthralgia, fever, myalgia, and headache. Since 2005 this virus has been responsible for an epidemic outbreak of unprecedented magnitude. By analogy with other alphaviruses, it is thought that cellular proteases are able to process the viral precursor protein E3E2 to produce the receptorbinding E2 protein that associates as a heterodimer with E1. Destabilization of the heterodimer by exposure to low pH allows viral fusion and infection. We show that among a large panel of proprotein convertases, membranous furin but also PC5B can process E3E2 from African CHIKV strains at the HRQRR 64 2ST site, whereas a CHIKV strain of Asian origin is cleaved at RRQRR 64 2SI by membranous and soluble furin, PC5A, PC5B, and PACE4 but not by PC7 or SKI-1. Using fluorogenic model peptides and recombinant convertases, we observed that the Asian strain E3E2 model peptide is cleaved most efficiently by furin and PC5A. This cleavage was also observed in CHIKV-infected cells and could be blocked by furin inhibitor decanoyl-RVKR-chloromethyl ketone. This inhibitor was compared with chloroquine for its ability to inhibit CHIKV spreading in myoblast cell cultures, a cell-type previously described as a natural target of this virus. Our results demonstrate the role of furin-like proteases in the processing of CHIKV particles and point out new approaches to inhibit this infection. Chikungunya virus (CHIKV)4 is a mosquito-transmitted Alphavirus belonging to the family Togaviridae, which was first reported in 1952 in Tanganyika. It is responsible for an acute infection of abrupt onset characterized by high fever, polyarthralgia, myalgia, headache, chills, and rash (1). The symptoms are generally of short duration (1 week), and recovery is often complete, although some patients have recurrent episodes for several weeks after infection (1, 2). CHIKV is endemic in Africa, India, and Southeast Asia and is transmitted by Aedes mosquitoes through an urban or sylvatic transmission cycle. In 2006 an outbreak of CHIKV fever occurred in numerous islands of the Indian Ocean (the Comoros, Mauritius, Seychelles, Madagascar, La Réunion, etc.) before jumping to India where an estimated 1.4 million cases have been reported (3-5). More recently, imported infections have been described in Europe, and around 200 endemic cases have been reported in Italy (6). Clinically, this CHIKV epidemic was accompanied by more severe symptoms than previous outbreaks, with reports of severe polyarthralgia and myalgia, complications, and deaths. In muscle biopsies from two infected adults we could identify cellular targets for CHIKV as muscle satellite cells (the muscle progenitor cells) and confirmed in vitro the susceptibility of these cells to CHIKV infection (7). Up until now no other cell targets have been identified in humans except for a recent report showing that fibroblast cells were infected in a fatal neonatal case (8). Other cell types such as ...

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Section: Discussionmentioning

confidence: 89%

Section: Furin-like Convertases and The Processing Of E3e2mentioning

confidence: 99%

Inhibition of Chikungunya Virus Infection in Cultured Human Muscle Cells by Furin Inhibitors

Ozden¹,

Lucas‐Hourani

Ceccaldi³

et al. 2008

Journal of Biological Chemistry

Self Cite

120

132

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“…Recently, a series of in vitro studies have suggested that the antimalarial drug chloroquine may have activity against influenza and other emerging respiratory pathogens 6 , 7 , 8 , 9 . Chloroquine is a lysosomotropic agent that accumulates in the endosomal compartment where it can impair the acidification of the endosome and prevent the conformational changes associated with viral fusion and release into the cytosol.…”

mentioning

confidence: 99%

Chloroquine is effective against influenza A virus in vitro but not in vivo

Vigerust

McCullers

2007

Influenza Resp Viruses

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Background Chloroquine is an inexpensive and widely available 9‐aminoquinolone used in the management of malaria. Recently, in vitro assays suggest that chloroquine may have utility in the treatment of several viral infections including influenza. Objectives We sought to test whether chloroquine is effective against influenza in vivo in relevant animal models. Methods The effectiveness of chloroquine at preventing or ameliorating influenza following viral challenge was assessed in established mouse and ferret disease models. Results Although active against influenza viruses in vitro, chloroquine did not prevent the weight loss associated with influenza virus infection in mice after challenge with viruses expressing an H1 or H3 hemagglutinin protein. Similarly, clinical signs and viral replication in the nose of ferrets were not altered by treatment. Conclusions Although in vitro results were promising, chloroquine was not effective as preventive therapy in vivo in standard mouse and ferret models of influenza virus infection. This dampens enthusiasm for the potential utility of the drug for humans with influenza.

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“…Mechanistic studies against VP35 and possibly other proteins should also be pursued and may be enlightened by the observation that both of these compounds also have reported activity against other viruses. For example, chloroquine is active against human coronavirus OC43 ( in vitro and in infected mice) as well as SARS ( in vitro ) 10, 30, 31 , while amodiaquine also inhibits dengue virus 2 replication and infectivity in vitro 11 .…”

Section: Discussionmentioning

confidence: 99%

A common feature pharmacophore for FDA-approved drugs inhibiting the Ebola virus

2014

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We are currently faced with a global infectious disease crisis which has been anticipated for decades. While many promising biotherapeutics are being tested, the search for a small molecule has yet to deliver an approved drug or therapeutic for the Ebola or similar filoviruses that cause haemorrhagic fever. Two recent high throughput screens published in 2013 did however identify several hits that progressed to animal studies that are FDA approved drugs used for other indications. The current computational analysis uses these molecules from two different structural classes to construct a common features pharmacophore. This ligand-based pharmacophore implicates a possible common target or mechanism that could be further explored. A recent structure based design project yielded nine co-crystal structures of pyrrolidinone inhibitors bound to the viral protein 35 (VP35). When receptor-ligand pharmacophores based on the analogs of these molecules and the protein structures were constructed, the molecular features partially overlapped with the common features of solely ligand-based pharmacophore models based on FDA approved drugs. These previously identified FDA approved drugs with activity against Ebola were therefore docked into this protein. The antimalarials chloroquine and amodiaquine docked favorably in VP35. We propose that these drugs identified to date as inhibitors of the Ebola virus may be targeting VP35. These computational models may provide preliminary insights into the molecular features that are responsible for their activity against Ebola virus in vitro and in vivo and we propose that this hypothesis could be readily tested.

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Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Abstract: Background: Severe acute respiratory syndrome (SARS) is caused by a newly discovered coronavirus (SARS-CoV). No effective prophylactic or post-exposure therapy is currently available.

Cited by 1,607 publications

References 26 publications

Inhibition of Chikungunya Virus Infection in Cultured Human Muscle Cells by Furin Inhibitors

Inhibition of Chikungunya Virus Infection in Cultured Human Muscle Cells by Furin Inhibitors

Chloroquine is effective against influenza A virus in vitro but not in vivo

A common feature pharmacophore for FDA-approved drugs inhibiting the Ebola virus

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