Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture

Wilde, Adriaan H. de; Jochmans, Dirk; Posthuma, Clara C.; Zevenhoven-Dobbe, Jessika C.; Nieuwkoop, Stefan van; Bestebroer, Theo M.; Hoogen, Bernadette G. van den; Neyts, Johan; Snijder, Eric J.

doi:10.1128/aac.03011-14

Cited by 687 publications

(712 citation statements)

References 84 publications

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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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Section: Discussionmentioning

confidence: 99%

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

2014

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“…Other compounds (chloroquine, chlorpromazine, loperamide, and lopinavir) inhibit virus replication (effective concentration 3-8 μmol/L) in-vitro, 98,99 although whether these drugs will be useful in patients is unknown. MERS-CoV-specific peptide fusion inhibitors, which function similarly to the HIV drug enfuvirtide, diminish virus replication in cultured cells, providing a novel approach to MERS treatment 100 .…”

Section: Treatmentmentioning

confidence: 99%

Untitled

2017

IJPSR

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“…Moreover, lopinavir has also been shown to have activity against severe acute respiratory syndrome (SARS) and, more recently, middle eastern respiratory syndrome (MERS) coronaviruses [67][68][69] .…”

Section: Hhuman Imunodeficiency Virus IV Protease Inhibitors (Hiv Pi's)mentioning

confidence: 99%

An overview of early investigational drugs for the treatment of human papilloma virus infection and associated dysplasia

Hampson

Martin-Hirsch

Hampson

2015

Expert Opinion on Investigational Drugs

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Introduction: Infection with hHigh-risk types of HPV (HR-HPV) isare the main aetiological agent forcause of invasive cervical cancer (ICC) from which there are >270,000 deaths per annum world-wide with over 85% of these occurring in lowresource countries. Ablative and excisional treatment modalities are restricted for use with high-grade pre-cancerous cervical disease with HPV infection and low-grade dysplasia is currently managed by a watch-and-wait policy.

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Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture

Cited by 687 publications

References 84 publications

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

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

Untitled

An overview of early investigational drugs for the treatment of human papilloma virus infection and associated dysplasia

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