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

Abstract

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.

Structure-Based Virtual Screening: Identification of a Novel NS2B-NS3 Protease Inhibitor with Potent Antiviral Activity against Zika and Dengue Viruses

“…The activity of their compound was comparable with our compound 1 in the cell culture model. Rachel et al identified the five-lipoxygenase-activating protein inhibitor, MK-591, inhibiting the ZIKV protease and infection in neural stem cells [ 27 ]. The IC 50 was higher (3 µM) than our compound 1.…”

A systems approach to enable effective team science from the internal research program of the National Center for Advancing Translational Sciences

“…A few recent examples illustrate these features in DPI's publications: a serosurvey of COVID-19; 25 molecular targets and pathways for organ level toxicity; 26 computational methods in metabolomics; 27 targeting cancer mutations with kinase inhibitors; 28 and therapeutic candidates for the Zika virus. 29 These publications [25][26][27][28][29] demonstrate the quality and public health impact of the research. Table 2 links the major findings of these studies to the performance metrics in Figure 2, providing a deeper analysis of the scientific contributions of the studies represented in this sample of DPI manuscripts.…”

Rapid Identification of Druggable Targets and the Power of the PHENotype SIMulator for Effective Drug Repurposing in COVID-19

“…For cost efficiency, validated predictive methods and assays for early elimination of potential drug candidates are of great value 59 . The overall efficiency (time, costs, safety) prompts to suggest implementing PHENSIM not only in viral acute pandemic settings 60 , but in additional curative and noncurative diseases, especially complex chronic disorders, where clinical trials are timeconsuming or impossible to reduce to practice. Optimally leveraging the power of pathway analysis by simulating host cell and tissue-specific infection and performing in silico drug selection, has a tremendous potential beyond COVID-19, with applicability to high global burden communicable diseases, translatable to pathogens of viral, bacterial and fungal origin, and potentially chronic disease such as inflamm-aging and diabetes.…”