Dataset Information

Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

ABSTRACT: In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ?6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.

SUBMITTER: Xu M

PROVIDER: S-EPMC5386783 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

Xu Miao M Lee Emily M EM Wen Zhexing Z Cheng Yichen Y Huang Wei-Kai WK Qian Xuyu X Tcw Julia J Kouznetsova Jennifer J Ogden Sarah C SC Hammack Christy C Jacob Fadi F Nguyen Ha Nam HN Itkin Misha M Hanna Catherine C Shinn Paul P Allen Chase C Michael Samuel G SG Simeonov Anton A Huang Wenwei W Christian Kimberly M KM Goate Alison A Brennand Kristen J KJ Huang Ruili R Xia Menghang M Ming Guo-Li GL Zheng Wei W Song Hongjun H Tang Hengli H

Nature medicine 20160829 10

In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV ...[more]

PMID: 27571349

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Project description:BackgroundConventional de novo drug design is costly and time consuming, making it accessible to only the best resourced research organizations. An emergent approach to new drug development is drug repurposing, in which compounds that have already gone through some level of clinical testing are examined for efficacy against diseases divergent than their original application. Repurposing of existing drugs circumvents the time and considerable cost of early stages of drug development, and can be accelerated by using software to screen existing chemical databases to identify suitable drug candidates.ResultsSmall-molecule Peptide-Influenced Drug Repurposing (SPIDR) was developed to identify small molecule drugs that target a specific receptor by exploring the conformational binding space of peptide ligands. SPIDR was tested using the potent and selective 16-amino acid peptide α-conotoxin MII ligand and the α3β2-nicotinic acetylcholine receptor (nAChR) isoform. SPIDR incorporates a genetic algorithm-based, heuristic search procedure, which was used to explore the ligand binding domain of the α3β2-nAChR isoform using a library consisting of 640,000 α-conotoxin MII peptide analogs. The peptides that exhibited the highest affinity for α3β2-nAChR were used as models for a small-molecule structure similarity search of the PubChem Compound database. SPIDR incorporates the SimSearcher utility, which generates shape distribution signatures of molecules and employs multi-level K-means clustering to insure fast database queries. SPIDR identified non-peptide drugs with estimated binding affinities nearly double that of the native α-conotoxin MII peptide.ConclusionsSPIDR has been generalized and integrated into DockoMatic v 2.1. This software contains an intuitive graphical interface for peptide mutant screening workflow and facilitates mapping, clustering, and searching of local molecular databases, making DockoMatic a valuable tool for researchers in drug design and repurposing.

Dataset Information

Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

Publications

Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

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