Treating Zika Infection: Repurposed Drugs Show Promise

Thursday, September 8, 2016

While wearing protective clothing, a researcher in a lab at NCATS dispenses Zika virus into trays for compound screening using procedures that follow strict biosafety standards.

Caption: An NCATS researcher dispenses Zika virus into trays for compound screening in a lab using procedures that follow strict biosafety standards. 
Credit: National Center for Advancing Translational Sciences, NIH

In response to the health threat posed by the recent outbreak of Zika virus in Latin America and its recent spread to Puerto Rico and Florida, researchers have been working at a furious pace to learn more about the mosquito-borne virus. Considerable progress has been made in understanding how Zika might cause babies to be born with unusually small heads and other abnormalities and in developing vaccines that may guard against Zika infection.

Still, there remains an urgent need to find drugs that can be used to treat people already infected with the Zika virus. A team that includes scientists at NIH’s National Center for Advancing Translational Sciences (NCATS) now has some encouraging news on this front. By testing 6,000 FDA-approved drugs and experimental chemical compounds on Zika-infected human cells in the lab, they’ve shown that some existing drugs might be repurposed to fight Zika infection and prevent the virus from harming the developing brain [1]. While additional research is needed, the new findings suggest it may be possible to speed development and approval of new treatments for Zika infection.

The latest study, published in Nature Medicine, builds on an earlier discovery by Guo-li Ming and Hongjun Song of Johns Hopkins University School of Medicine, Baltimore, and Hengli Tang of Florida State University, Tallahassee, that Zika virus readily infects human neural progenitor cells in lab dishes. That team also found that Zika infection causes many of those essential brain cells to die, providing a possible explanation for microcephaly in newborn babies exposed to the virus while in their mothers’ wombs.

In the new work, Ming, Song, and Tang joined forces with NCATS researcher Wei Zheng and colleagues to screen for drug compounds that might have the potential to limit Zika’s ability to infect neural progenitor cells or to prevent those Zika-infected cells from dying. By taking advantage of high-tech, drug-screening robots and vast libraries of drug compounds at NCATS, the team was able to test the effects of thousands of potential drug candidates on Zika-infected human cells in a matter of weeks.

The initial screen, using procedures that follow strict biosafety standards, generated a list of more than 100 compounds with potential promise for treating Zika infection. Further examination of those compounds in Tang’s lab in Tallahassee trimmed the list down to three lead candidates.

The first is an investigational drug called emricasan, which is currently in clinical trials for people with liver injury or fibrosis. The researchers found that emricasan protects neural progenitor cells from dying following infection by the Zika virus, both in two-dimensional cell layers and in three-dimensional “organoids” that mimic important structures in the developing brain.

Once inside a neural progenitor cell, Zika virus takes over the cell’s machinery to produce and release more Zika to infect more cells. The two other candidate compounds protected neural cells by substantially limiting that ability of the virus to produce more copies of itself. Those drugs include PHA-690509, an investigational cyclin-dependent kinase (CDK) inhibitor that has been studied for use in treating cancer, and niclosamide, an FDA-approved drug that has been used for many years to treat tapeworms. Though caution and additional study is warranted, the researchers note that niclosamide might even be considered for use in pregnant women.

The researchers went on to test another 27 CDK inhibitors and found that many of them also successfully inhibited Zika virus replication. The findings suggest a new target pathway for anti-Zika drug development. The researchers also showed early evidence that a combination treatment, including one neuroprotective compound and one anti-viral compound, might offer the best protection for neural progenitor cells against Zika virus.

The results identify lead compounds for continued drug development against Zika virus, which could aid in efforts to reduce the risks associated with Zika infection. More broadly, the new work also demonstrates the promise of large-scale screens of existing drug compounds as a means to speed the discovery of new treatments to address many emerging infectious disease threats. In fact, the NCATS team previously used this same approach to identify 53 compounds with promise for treating Ebola virus infection [2].

The research team says they’ll test the effects of their compounds in animals infected with Zika virus before moving on to clinical trials in human volunteers. To encourage other researchers around the world to pursue additional treatment strategies for Zika, they’ve also made all of their data freely available.

References:

[1] Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, Tcw J, Kouznetsova J, Ogden SC, Hammack C, Jacob F, Nguyen HN, Itkin M, Hanna C, Shinn P, Allen C, Michael SG, Simeonov A, Huang W, Christian KM, Goate A, Brennand KJ, Huang R, Xia M, Ming GL, Zheng W, Song H, Tang H. Nat Med. 2016 Aug 29. [Epub ahead of print]

[2] Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs. Kouznetsova J, Sun W, Martínez-Romero C, Tawa G, Shinn P, Chen CZ, Schimmer A, Sanderson P, McKew JC, Zheng W, García-Sastre A. Emerg Microbes Infect. 2014 Dec;3(12):e84. 2014 Dec 17.

Links:

Zika Virus (Centers for Disease Control and Prevention)

Repurposing Drugs (National Center for Advancing Translational Sciences/NIH)

Hongjun Song (Johns Hopkins University, Baltimore)

Guo-li Ming (Johns Hopkins University, Baltimore)

Hengli Tang (Florida State University, Tallahassee)

Wei Zheng (National Center for Advancing Translational Sciences, Bethesda, MD)

NIH Support: National Center for Advancing Translational Sciences; National Institute of Neurological Disorders and Stroke; National Institute of Mental Health; National Institute on Aging; National Institute of Allergy and Infectious Diseases

Category: Science

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