Biological Activity-Based Modeling Identifies Antiviral Leads against SARS-CoV-2

Scientists report a biological activity-based modeling approach, in which compound activity profiles established across multiple assays were used as signatures to predict compound activity in other assays or against a new target.
[Nature Biotechnology]
Huang, R., Xu, M., Zhu, H., Chen, C. Z., Zhu, W., Lee, E. M., He, S., Zhang, L., Zhao, J., Shamim, K., Bougie, D., Huang, W., Xia, M., Hall, M. D., Lo, D., Simeonov, A., Austin, C. P., Qiu, X., Tang, H., & Zheng, W. (2021). Biological activity-based modeling identifies antiviral leads against SARS-CoV-2. Nature Biotechnology, 1–7. https://doi.org/10.1038/s41587-021-00839-1 Cite
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A Genetically Stable Zika Virus Vaccine Candidate Protects Mice against Virus Infection and Vertical Transmission

The authors generated a Zika virus mutant, ZE4B-36, which combined mutations in both E glycosylation and NS4B P36.
[npj Vaccines]
Adam, A., Fontes-Garfias, C. R., Sarathy, V. V., Liu, Y., Luo, H., Davis, E., Li, W., Muruato, A. E., Wang, B., Ahatov, R., Mahmoud, Y., Shan, C., Osman, S. R., Widen, S. G., Barrett, A. D. T., Shi, P.-Y., & Wang, T. (2021). A genetically stable Zika virus vaccine candidate protects mice against virus infection and vertical transmission. Npj Vaccines, 6(1), 1–11. https://doi.org/10.1038/s41541-021-00288-6 Cite
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Structural Basis for Antibody Inhibition of Flavivirus NS1–Triggered Endothelial Dysfunction

Scientists present three crystal structures of full-length dengue virus NS1 complexed with a flavivirus–cross-reactive, NS1-specific monoclonal antibody, 2B7, at resolutions between 2.89 and 3.96 angstroms. These structures reveal a protective mechanism by which two domains of NS1 are antagonized simultaneously.
[Science]
Biering, S. B., Akey, D. L., Wong, M. P., Brown, W. C., Lo, N. T. N., Puerta-Guardo, H., Sousa, F. T. G. de, Wang, C., Konwerski, J. R., Espinosa, D. A., Bockhaus, N. J., Glasner, D. R., Li, J., Blanc, S. F., Juan, E. Y., Elledge, S. J., Mina, M. J., Beatty, P. R., Smith, J. L., & Harris, E. (2021). Structural basis for antibody inhibition of flavivirus NS1–triggered endothelial dysfunction. Science, 371(6525), 194–200. https://doi.org/10.1126/science.abc0476 Cite
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Multiscale 3D Phenotyping of Human Cerebral Organoids

Brain organoids grown from human pluripotent stem cells self-organize into cytoarchitectures resembling the developing human brain. Investigators present the SCOUT pipeline for automated multiscale comparative analysis of intact cerebral organoids.
[Scientific Reports]
Albanese, A., Swaney, J. M., Yun, D. H., Evans, N. B., Antonucci, J. M., Velasco, S., Sohn, C. H., Arlotta, P., Gehrke, L., & Chung, K. (2020). Multiscale 3D phenotyping of human cerebral organoids. Scientific Reports, 10(1), 21487. https://doi.org/10.1038/s41598-020-78130-7 Cite
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Super Resolution Microscopy and Deep Learning Identify Zika Virus Reorganization of the Endoplasmic Reticulum

Using 3D super resolution microscopy, ZIKV infection was shown to induce the formation of dense tubular matrices associated with viral replication in the central endoplasmic reticulum.
[Scientific Reports]
Long, R. K. M., Moriarty, K. P., Cardoen, B., Gao, G., Vogl, A. W., Jean, F., Hamarneh, G., & Nabi, I. R. (2020). Super resolution microscopy and deep learning identify Zika virus reorganization of the endoplasmic reticulum. Scientific Reports, 10(1), 20937. https://doi.org/10.1038/s41598-020-77170-3 Cite
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CD8+ T Cells Mediate Protection against Zika Virus Induced by an NS3-Based Vaccine

Scientists report induction of a protective anti-ZIKV CD8+ T cell response in the HLA-B*0702 Ifnar1−/− transgenic mice using an alphavirus-based replicon RNA vaccine expressing ZIKV nonstructural protein NS3, a potent T cell antigen.
[Science Advances]
Ngono, A. E., Syed, T., Nguyen, A.-V., Regla-Nava, J. A., Susantono, M., Spasova, D., Aguilar, A., West, M., Sparks, J., Gonzalez, A., Branche, E., DeHart, J. L., Vega, J. B., Karmali, P. P., Chivukula, P., Kamrud, K., Aliahmad, P., Wang, N., & Shresta, S. (2020). CD8+ T cells mediate protection against Zika virus induced by an NS3-based vaccine. Science Advances, 6(45), eabb2154. https://doi.org/10.1126/sciadv.abb2154 Cite
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Multimerization of Zika Virus-NS5 Causes Ciliopathy and Forces Premature Neurogenesis

Investigators showed that the Zika virus-NS5 protein interacts with host proteins at the base of the primary cilia in neural progenitor cells, causing an atypical non-genetic ciliopathy and premature neuron delamination.
[Cell Stem Cell]
Saade, M., Ferrero, D. S., Blanco-Ameijeiras, J., Gonzalez-Gobartt, E., Flores-Mendez, M., Ruiz-Arroyo, V. M., Martínez-Sáez, E., Ramón y Cajal, S., Akizu, N., Verdaguer, N., & Martí, E. (2020). Multimerization of Zika Virus-NS5 Causes Ciliopathy and Forces Premature Neurogenesis. Cell Stem Cell. https://doi.org/10.1016/j.stem.2020.10.002 Cite
AbstractPress ReleaseGraphical Abstract
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Lyn Kinase Regulates Egress of Flaviviruses in Autophagosome-Derived Organelles

Scientists investigated how flaviviruses exploit Src family kinases for exit from infected cells. They identifyied Lyn as a critical component for secretion of Dengue and Zika infectious particles and their corresponding virus like particles
[Nature Communications]
Li, M. Y., Naik, T. S., Siu, L. Y. L., Acuto, O., Spooner, E., Wang, P., Yang, X., Lin, Y., Bruzzone, R., Ashour, J., Evans, M. J., & Sanyal, S. (2020). Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles. Nature Communications, 11(1), 5189. https://doi.org/10.1038/s41467-020-19028-w Cite
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Identification of a Pocket Factor That Is Critical to Zika Virus Assembly

Investigators used subvolume refinement to achieve a 3.4 Å resolution structure and identify two distinct lipid moieties. The first arose from the inner leaflet and was coordinated by hydrophobic residues of the M and E transmembrane helices that form a binding pocket not previously characterized.
[Nature Communications]
DiNunno, N. M., Goetschius, D. J., Narayanan, A., Majowicz, S. A., Moustafa, I., Bator, C. M., Hafenstein, S. L., & Jose, J. (2020). Identification of a pocket factor that is critical to Zika virus assembly. Nature Communications, 11(1), 4953. https://doi.org/10.1038/s41467-020-18747-4 Cite
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SARS-CoV2-Mediated Suppression of NRF2-Signaling Reveals Potent Antiviral and Anti-Inflammatory Activity of 4-Octyl-Itaconate and Dimethyl Fumarate

Researchers uncovered that NRF2 agonists 4-octyl-itaconate and the clinically approved dimethyl fumarate induced a cellular antiviral program that potently inhibited replication of SARS-CoV2 across cell lines.
[Nature Communications]
Olagnier, D., Farahani, E., Thyrsted, J., Blay-Cadanet, J., Herengt, A., Idorn, M., Hait, A., Hernaez, B., Knudsen, A., Iversen, M. B., Schilling, M., Jørgensen, S. E., Thomsen, M., Reinert, L. S., Lappe, M., Hoang, H.-D., Gilchrist, V. H., Hansen, A. L., Ottosen, R., … Holm, C. K. (2020). SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nature Communications, 11(1), 4938. https://doi.org/10.1038/s41467-020-18764-3 Cite
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Inhibition of Na+/K+ ATPase Blocks Zika Virus Infection in Mice

Investigators showed that two FDA-approved Na+/K+-ATPase inhibitors, ouabain and digoxin, could block Zika virus infection at the replication stage by targeting Na+/K+-ATPase.
[Communications Biology]
Guo, J., Jia, X., Liu, Y., Wang, S., Cao, J., Zhang, B., … Wang, W. (2020). Inhibition of Na + /K + ATPase blocks Zika virus infection in mice. Communications Biology, 3(1), 1–8. https://doi.org/10.1038/s42003-020-1109-8 Cite
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