Journal Article

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

Brimacombe, Kyle, Simeonov, Anton, Lee, Myoung-Hwa, Padmanabhan, Radhakrishnan, Abrams, Rachel P. M., Li, Wenxue, Balasubramanian, Anuradha, Hall, Matthew D., Yasgar, Adam, Teramoto, Tadahisa, Dorjsuren, Dorjbal, Zakharov, Alexey V., Steiner, Joseph P., Nath, Avindra, Malik, Nasir, Eastman, Richard T., Bachani, Muzna, Jadhav, Ajit

2020

Overview

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 paradigmhave 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.

• Publisher: National Academy of Sciences
• Subject: Animals / Antibiotics / Antiviral Agents - analysis / Antiviral Agents - pharmacology / Antiviral Agents - therapeutic use / Artificial Intelligence / Biological Sciences / Chlorocebus aethiops / Disease Models, Animal / Drug Evaluation, Preclinical / FDA approval / High-Throughput Screening Assays / Immunocompetence / Infections / Inhibitory Concentration 50 / Lipoxygenase / Medical Sciences / Methacycline / Methacycline - pharmacology / Mice, Inbred C57BL / Molecular structure / Neural stem cells / Neurological complications / Protease / Protease inhibitors / Protease Inhibitors - analysis / Protease Inhibitors - pharmacology / Protease Inhibitors - therapeutic use / Proteinase inhibitors / Public health / Quantitative Structure-Activity Relationship / Small Molecule Libraries / Stem cell transplantation / Stem cells / Tetracyclines / Vector-borne diseases / Vero Cells / Viral infections / Viruses / Zika virus / Zika Virus - drug effects / Zika Virus Infection - drug therapy / Zika Virus Infection - virology