marinopyrrole-a and Zika-Virus-Infection

Flavivirus and enterovirus can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases or even death. Since effective vaccine is currently unavailable against most of these deadly viruses, antiviral chemical drugs remain in urgent need. To meet this unmet demand, we developed a series of 10,10'-bis(trifluoromethyl) marinopyrrole A derivates bearing various substituents at C5'-positions, which exhibited impressive in vitro activities against flaviviruses (ZIKV, DENV, YFV, JEV) and enteroviruses (EV71, CA6, CA16). The lead compound 10,10'-bis(trifluoromethyl) marinopyrrole A 3 was highly effective against enteroviruses EV71 and CA16 in cultured cells, but with low inhibitory activities against flavivirus. Elaborately modified from compound 3, compounds 32 and 33 with sulfhydryl aliphatic chains were found as promising ZIKV and DENV inhibitor; pyrazine-containing compound 19 is a potent broad-spectrum flavivirus inhibitor; thiophene compound 15 exhibited prominent selective inhibitory effect against JEV-SA14, YFV-17D, in addition to broad-spectrum enterovirus inhibitory effect. These results thus suggest that the 5'-sulfhydryl derivates of 10,10'-bis(trifluoromethyl) marinopyrrole A may be promising lead compounds for the development of novel anti-flavivirus and anti-enterovirus drugs.

Topics: Antiviral Agents; Enterovirus; Enterovirus Infections; Flavivirus; Humans; Pyrroles; Zika Virus; Zika Virus Infection

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.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection