Majority of flaviviruses are significant human pathogens. Zika virus (ZIKV), a member of the flavivirus family, starts to emerge and causes severe human diseases. The World Health Organization (WHO) has declared ZIKV as a global public health emergency. There is currently neither effective vaccine nor specific therapy for ZIKV. For flaviviruses, a single viral polyprotein precursor is synthesized from the viral genome during infection of the host cell. The virus encodes its own protease, which works together with host proteases to cleave the protein precursor into its component proteins. The viral protease is composed of viral proteins NS2B and NS3. This viral protease is essential for virus assembly and replication. Using a high throughput screening assay, we identified several existing drugs, including niclosamide and nitazoxanide, that are potent and broad-spectrum flavivirus inhibitors. These drugs inhibited flavivirus protease via an orthosteric inhibition mechanism, by blocking the interactions between viral protease components NS2B and NS3. The major goal of this proposal is to perform reformulation, in vivo pharmacokinetics and efficacy studies to establish whether these two drugs, niclosamide and nitazoxanide, are effective in ZIKV animal model. These studies are essential for drug repurposing. The approval of new compounds as drugs by governmental drug administration agencies requires significant effort, time, and expense. If drugs that are already approved for treatment have additional capabilities that can be exploited therapeutically, repurposing them is the fastest route to develop new therapies.
Flaviviruses such as West Nile virus, Dengue virus, and Zika virus are worldwide endemic arthropod-borne human pathogens that infect over 200 million and kill over 100,000 people per year. Despite effective vaccines for JEV, YFV, and TBEV, difficulty in vaccinating large at risk populations and a lack of safe vaccines for devastating viruses such as Zika necessitate development of antiviral therapeutics to combat severe flavivirus infections. The proposed work will repurpose existing drugs for management of ZIKV infections.
|Li, Zhong; Sakamuru, Srilatha; Huang, Ruili et al. (2018) Erythrosin B is a potent and broad-spectrum orthosteric inhibitor of the flavivirus NS2B-NS3 protease. Antiviral Res 150:217-225|
|Li, Zhong; Brecher, Matthew; Deng, Yong-Qiang et al. (2017) Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction. Cell Res 27:1046-1064|