Therapeutic candidates for the Zika virus identified by a high-throughput screen for Zika protease inhibitors.

Autor:	Abrams RPM; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892., Yasgar A; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850., Teramoto T; Department of Microbiology and Immunology, Georgetown University, Washington, DC 20057., Lee MH; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892., Dorjsuren D; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850., Eastman RT; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850., Malik N; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892., Zakharov AV; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850., Li W; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892., Bachani M; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892., Brimacombe K; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850., Steiner JP; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892., Hall MD; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850., Balasubramanian A; Department of Microbiology and Immunology, Georgetown University, Washington, DC 20057., Jadhav A; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850., Padmanabhan R; Department of Microbiology and Immunology, Georgetown University, Washington, DC 20057 rp55@georgetown.edu asimeono@mail.nih.gov natha@ninds.nih.gov., Simeonov A; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850; rp55@georgetown.edu asimeono@mail.nih.gov natha@ninds.nih.gov., Nath A; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892; rp55@georgetown.edu asimeono@mail.nih.gov natha@ninds.nih.gov.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Dec 08; Vol. 117 (49), pp. 31365-31375. Date of Electronic Publication: 2020 Nov 23.
DOI:	10.1073/pnas.2005463117
Abstrakt:	When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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