The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Parallel shRNA and CRISPR-Cas9 screens enable antiviral drug target identification
Open accessAbstract
Broad spectrum antiviral drugs targeting host processes could potentially treat a wide range of viruses while reducing the likelihood of emergent resistance. Despite great promise as therapeutics, such drugs remain largely elusive. Here we use parallel genome-wide high-coverage shRNA and CRISPR-Cas9 screens to identify the cellular target and mechanism of action of GSK983, a potent broad spectrum antiviral with unexplained cytotoxicity1–3. We show that GSK983 blocks cell proliferation and dengue virus replication by inhibiting the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH). Guided by mechanistic insights from both genomic screens, we found that exogenous deoxycytidine markedly reduces GSK983 cytotoxicity but not antiviral activity, providing an attractive novel approach to improve the therapeutic window of DHODH inhibitors against RNA viruses. Together, our results highlight the distinct advantages and limitations of each screening method for identifying drug targets and demonstrate the utility of parallel knockdown and knockout screens for comprehensively probing drug activity.
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The global distribution and burden of dengue
Bhatt, S., Gething, P. W., Brady, O. J., Messina, J. P., Farlow, A. W., Moyes, C. L., Drake, J. M., Brownstein, J. S., Hoen, A. G., Sankoh, O., et al. (2013) · Nature · doi:10.1038/nature12060 · Cited by 10,037
RNA-Guided Human Genome Engineering via Cas9
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Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool
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Genome-scale CRISPR-Cas9 knockout screening in human cells
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CRISPR-Mediated Modular RNA-Guided Regulation of Transcription in Eukaryotes
Gilbert, L. A., Larson, M. H., Morsut, L., Liu, Z., Brar, G. A., Torres, S. E., Stern-Ginossar, N., Brandman, O., Whitehead, E. H., Doudna, J. A., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.044 · Cited by 3,696
Self-citationGenome-Scale CRISPR-Mediated Control of Gene Repression and Activation
Gilbert, L. A., Horlbeck, M. A., Adamson, B., Villalta, J. E., Chen, Y., Whitehead, E. H., Guimaraes, C., Panning, B., Ploegh, H. L., Bassik, M. C., et al. (2014) · Cell · doi:10.1016/j.cell.2014.09.029 · Cited by 2,728
Self-citationBar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., & Sabatini, D. M. (2013) · Science · doi:10.1126/science.1232044 · Cited by 1,080
Regulation of mTORC1 by amino acids
Bar-Peled, L., & Sabatini, D. M. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.03.003 · Cited by 773
High-throughput RNAi screening in cultured cells: a user's guide
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A Systematic Mammalian Genetic Interaction Map Reveals Pathways Underlying Ricin Susceptibility
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Cited by
Oughtred, R., Rust, J., Chang, C., Breitkreutz, B., Stark, C., Willems, A., Boucher, L., Leung, G., Kolas, N., Zhang, F., et al. (2021) · Protein Science · doi:10.1002/pro.3978 · Cited by 1,858
Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., et al. (2019) · doi:10.1101/722827 · Cited by 1,414
Self-citationMarschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0566-1 · Cited by 1,384
Self-citationAm I ready for CRISPR? A user's guide to genetic screens
Doench, J. G. (2018) · Nature Reviews Genetics · doi:10.1038/nrg.2017.97 · Cited by 452
Systematic comparison of CRISPR/Cas9 and RNAi screens for essential genes
Morgens, D. W., Deans, R. M., Li, A., & Bassik, M. C. (2016) · Nature Biotechnology · doi:10.1038/nbt.3567 · Cited by 401
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Metadata
- Authors
- Deans, R. M., Morgens, D. W., Ökesli, A., Pillay, S., Horlbeck, M. A., Kampmann, M., Gilbert, L. A., Li, A., Mateo, R., Smith, M., Glenn, J. S., Carette, J. E., Khosla, C., & Bassik, M. C.
- Venue
- Nature Chemical Biology
- Published
- 2016-03-28
- Volume
- 12
- Issue
- 5
- Pages
- 361-366
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2334877168
- Cited by
- 182
- References
- 11
- FWCI
- 12.94
- Type
- journal article
- Language
- en
- Open access
- green
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- Deans, R. M., Morgens, D. W., Ökesli, A., Pillay, S., Horlbeck, M. A., Kampmann, M., Gilbert, L. A., Li, A., Mateo, R., Smith, M., Glenn, J. S., Carette, J. E., Khosla, C., & Bassik, M. C. (2016). Parallel shRNA and CRISPR-Cas9 screens enable antiviral drug target identification. Nature Chemical Biology. https://doi.org/10.1038/nchembio.2050
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