Repurposed Pharmaceutical Compositions with Anti-flaviviral Activity including Zika

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High throughput screening has led to identification of several existing drugs that can inhibit the viral protease function of Zika.

Dr. Li and his team found that these drugs are broad spectrum flavivirus inhibitors. The candidate drugs can significantly inhibit the growth and replication of not only Zika virus, but also Dengue virus, West Nile virus, Japanese encephalitis virus, Yellow fever virus, St. Louis encephalitis virus, and Powassan virus, with efficacies from micromolar to nanomolar. Dr. Li’s team further demonstrated that these drugs inhibit virus replication via a mechanism of inhibition of the viral protease function. The protease complex NS2BNS3 plays essential roles during flaviviral polyprotein processing, and thus represents an attractive drug target. The compositions include: niclosamide, temoporfin, nitazoxanide, tizoxanide, erythrosin B, methylene blue.

Background: Dr. Hongmin Li and his NIH collaborators have identified several existing drugs and compounds that demonstrate activity against Zika. These compounds, which have the potential for drug development, were discovered by screening an NIH library of compounds with an assay and methods developed by the Wadsworth Center. The anti-Zika activity of two of these compounds has been corroborated in an independent study at the University of Florida. HRI has been awarded a United States patent on these “repurposed” drugs. Repurposing can provide one of the fasted routes for establishing treatment for new disease outbreaks, since the drugs often have known properties, safety data or regulatory approvals. One of the compounds identified by Dr. Li is an FDA-approved drug – Niclosamide. Additional work has identified analogs that improve the effectiveness of Niclosamide for anti-flaviviral use. The analogs are also patented and are further described in a separate document at:

A 2015 -2016 outbreak of Zika virus, a flavivirus closely related to other flaviviruses that have caused outbreaks, e.g., Dengue, West Nile and Yellow fever, highlights the need for therapeutics for management of flavivirus infections. Over several years, Dr. Hongmin Li, developed high throughput screening assays to identify inhibitors for the viral protease which is an essential and conserved enzyme encoded by all flaviviruses to process viral polyprotein. In collaboration with National Center for Advancing Translational Sciences, Dr. Li’s team screened a pharmaceutical drug library that harbors 2,816 existing drugs already approved by FDA in the US or other countries, or in clinical trials for other applications. Drug repurposing is the quickest way to respond to a worldwide emergency such as the Zika outbreak. Several drugs identified by Dr. Li and his team are approved drugs with good safety profiles and importantly for Zika, have been used previously to treat pregnant women successfully.  


  • Treatment of flavivirus infections including Zika
  • Potential prophylactic use to prevent replication of Zika and other flavivirus.


  • Existing clinical and safety data is available for some of the compositions.     

Benefits:  Inhibitors targeted to the NS2B-binding site on NS3 have broad-spectrum anti-flaviviral activity, as this site is conserved among flavivirus NS3 proteases. In support of this idea, we also tested the ability of temoporfin and niclosamide to inhibit DENV2, WNV, JEV, and YFV infection. Our results clearly demonstrate that both temoporfin and niclosamide are broad-spectrum inhibitors against all flaviviruses tested in addition to ZIKV and exhibit similar potencies. Overall, our results demonstrate that flaviviral proteases can be targeted at an orthosteric site and provide a starting point for further development of orthosteric inhibitors. These findings establish the efficacy of our antiviral drugs to efficiently eliminate infection of ZIKV from human placenta, stem, and progenitor cells, demonstrating a potential means of minimizing the risk of fetal-acquired microcephaly resulting from ZIKV infection of pregnant women63. Although further experimentation will be required to establish whether these drugs can be used prophylactically in treatment of ZIKV-infected patients, including pregnant women, the excellent safety profiles of niclosamide and nitazoxanide suggest such a possibility.  

Patents and Licensing:  U.S. Patent 11,491,123- Pharmaceutical Compositions with Anti-flaviviral Activity See also U.S. Patent Application No.: 17/384,051

Key Words: Zika, Dengue virus, West Nile virus, Japanese encephalitis virus, Yellow fever virus, St. Louis encephalitis virus, Powassan virus, niclosamide, temoporfin, nitazoxanide, tizoxanide, erythrosin B, methylene blue, photodynamic, Microcephaly, ; Essential Drugs, FDA approved, Peptide Hydrolases, Pharmaceutical Preparations, Polyproteins, Dengue Hemorrhagic Fever, Dengue Vaccine, Pregnancy; Pregnant Women, Protease Inhibitor, Protein Precursors, West Nile Encephalitis, Tick-Borne Encephalitis Virus, novel therapeutics, antiviral,  protease inhibitor


Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction. Li, Z., Brecher, M., Deng, YQ. et al. Cell Res 27, 1046–1064 (2017).

Broad Spectrum Antiviral Agent Niclosamide and Its Therapeutic Potential   Jimin Xu, Pei-Yong Shi, Hongmin Li, and Jia Zhou ACS Infectious Diseases 2020 6 (5), 909-915    DOI: 10.1021/acsinfecdis.0c00052

Erythrosin B is a potent and broad-spectrum orthosteric inhibitor of the flavivirus NS2B-NS3 protease. Li Z, Sakamuru S, Huang R, Brecher M, Koetzner CA, Zhang J, Chen H, Qin CF, Zhang QY, Zhou J, Kramer LD, Xia M, Li H. Antiviral Res. 2018 Feb;150:217-225.   DOI: 10.1016/j.antiviral.2017.12.018. Epub 2017 Dec 27. PMID: 29288700; PMCID: PMC5892443.

In vitro and in vivo characterization of erythrosin B and derivatives against Zika virus.  Li Z, Xu J, Lang Y, Wu X, Hu S, Samrat SK, Tharappel AM, Kuo L, Butler D, Song Y, Zhang QY, Zhou J, Li H.  Acta Pharm Sin B. 2022 Apr;12(4):1662-1670. Epub 2021 Oct 22. PMID: 35847519; PMCID: PMC9279632. DOI: 10.1016/j.apsb.2021.10.017

Methylene blue is a potent and broad-spectrum inhibitor against Zika virus in vitro and in vivo, Zhong Li, Yuekun Lang, Srilatha Sakamuru, Subodh Samrat, Nicole Trudeau, Lili Kuo, Natasha Rugenstein, Anil Tharappel, Lianna D’Brant, Cheri A. Koetzner, Saiyang Hu, Jing Zhang, Ruili Huang, Laura D. Kramer, David Butler, Menghang Xia & Hongmin Li (2020)  Emerging Microbes & Infections, 9:1, 2404-2416, DOI: 10.1080/22221751.2020.1838954

JMX0207, a Niclosamide Derivative with Improved Pharmacokinetics, Suppresses Zika Virus Infection Both In Vitro and In Vivo Zhong Li, Jimin Xu, Yuekun Lang, et al Hongmin Li ACS Infectious Diseases 2020 6 (10), 2616-2628 DOI: 10.1021/acsinfecdis.0c00217 Inventors: Hongmin Li, Laura D. Kramer, Zhong Li, Ruili Huang, Menghang Xia

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