A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents

Madrid, Peter B.; Chopra, Sidharth; Manger, Ian D.; Gilfillan, Lynne; Keepers, Tiffany R.; Shurtleff, Amy C.; Green, Carol E.; Iyer, Lalitha; Dilks, Holli H.; Davey, Robert A.; Kolokoltsov, Andrey A.; Carrión, Ricardo; Bavari, Sina; Panchal, Rekha G.; Warren, Travis K.; Wells, Jay; Moos, Walter H.; Burke, RaeLyn L.; Tanga, Mary J.

doi:10.1371/journal.pone.0060579

Cited by 230 publications

(317 citation statements)

References 39 publications

(42 reference statements)

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“…These molecules were similar to the FDA benzimidazole and aminoquinoline 8, 9 compounds that were active against EBOV. Another good example is the recent in silico docking of 5.4 million drug-like compounds docked in the viral protein VP35 protein 15 .…”

Section: Introductionmentioning

confidence: 72%

“…Previously estradiol was suggested to be active in the EBOV pseudotype assay in vitro 8 . In addition, dibucaine was also retrieved (Fit value 1.58) which was also active in the EBOV pseudotype assay 8 . Amodiaquine, chloroquine, clomiphene and toremifene can be used as positive controls for future screens.…”

Section: Resultsmentioning

confidence: 99%

“…Two papers from 2013 described compounds active as inhibitors of different EBOV strains in vitro and in vivo , namely amodiaquine and chloroquine in one study 8 , clomiphene and toremifene in another 9 . These active molecules were used as they have both in vitro and in vivo activity to build a common features pharmacophore with Discovery Studio 4.1 (Biovia, San Diego, CA) from 3D conformations of the molecules generated with the CAESAR algorithm.…”

Section: Methodsmentioning

confidence: 99%

“…In both cases over 300 hits were retrieved initially. The van der Waals surface of amodiaquine (which was more potent than chloroquine 8 ) was added to limit the number of hits retrieved 17– 19 .…”

Section: Methodsmentioning

confidence: 99%

“…Two recent studies utilized high-throughput screens of a subset of FDA approved drugs against different EBOV strains (Zaire and Sudan) in vitro and in vivo . These independent reports suggested the promise of the antimalarials amodiaquine and chloroquine in one study 8 , while the selective estrogen receptor modulators (SERMs) clomiphene and toremifene were active in another 9 . Chloroquine to date has not progressed beyond the mouse EBOV model used in these studies.…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2014

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Viral glycoproteomes: technologies for characterization and outlook for vaccine design

et al. 2018

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It has long been known that surface proteins of most enveloped viruses are covered with glycans. It has furthermore been demonstrated that glycosylation is essential for propagation and immune evasion for many viruses. The recent development of high-resolution mass spectrometry techniques has enabled identification not only of the precise structures but also the positions of such post-translational modifications on viruses, revealing substantial differences in extent of glycosylation and glycan maturation for different classes of viruses. In-depth characterization of glycosylation and other post-translational modifications of viral envelope glycoproteins is essential for rational design of vaccines and antivirals. In this Review, we provide an overview of techniques used to address viral glycosylation and summarize information on glycosylation of enveloped viruses representing ongoing public health challenges. Furthermore, we discuss how knowledge on glycosylation can be translated to means to prevent and combat viral infections.

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Retroviral Pseudotypes – From Scientific Tools to Clinical Utility

Temperton

Wright

Scott

2015

Encyclopedia of Life Sciences

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Retroviral pseudotypes are important research and diagnostic tools for basic and clinical virology studies, facilitating the detailed investigation of individual genes, cellular receptors, antibody responses, serosurveillance and antiviral therapies. Importantly, pseudotypes enable the study of highly pathogenic viruses, without the need for high containment. Their use as gene therapy vectors is widely documented, but other uses, once less well known, are becoming more prominent. The substitution of envelope proteins expressed on the virion surface enables pseudotypes to be employed as surrogates for wildtype viruses in antibody neutralisation or antiviral screening assays and for the study of cell–virus receptor interactions. In addition, they are increasingly being utilised as vaccine immunogens, expressing the antigen either on the particle surface or as a transfer gene for cellular expression. These studies demonstrate the potential for using pseudotypes for both scientific and clinical applications. Key Concepts Students will learn: What are retroviral pseudotypes. How they are constructed and titrated. The common elements that comprise a retroviral pseudotype. How retroviral pseudotypes can be used to deliver genes. How they can be used as tools for the study of viral attachment, entry and receptor identification. About using pseudotypes as surrogate viruses in antibody neutralisation assays. The use of pseudotypes to measure vaccine immunogenicity and screen for antiviral activity and resistance. How pseudotypes can be used as experimental vaccines.

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A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents

Cited by 230 publications

References 39 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

Viral glycoproteomes: technologies for characterization and outlook for vaccine design

Retroviral Pseudotypes – From Scientific Tools to Clinical Utility

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