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Methacycline Shows Promise Against Zika Virus in Preclinical Testing

Article In Brief

Intravenous delivery of methacycline significantly reduced the amount of Zika virus in a mouse model and the severity of virus-induced motor deficits.

An old drug may have a new trick. The antibiotic methacycline, first developed in 1965, was identified in a search of over 130,000 small molecules as likely to block transmission and survival of the Zika virus. It did just that when placed in a solution of neural stem cells infected with the virus. And in a mouse model, intravenous delivery of methacycline significantly reduced the amount of virus in their brains and the severity of virus-induced motor deficits.

The study, published in the Proceedings of the National Academy of Sciences on December 8, came on the heels of another paper, in Lancet Neurology, looking at the effects of dual infection with Zika and chikungunya viruses. The observational study of patients from northeast Brazil found that co-occurrence was associated with a greatly increased risk of severe neurological complications compared to mono-infection. Previous papers have also found that simultaneous infection with more than one arbovirus is associated with an increased risk of adverse clinical outcomes.

Zika virus is known to cause microcephaly in the fetus due to its ability to cross the placenta and infect the neural stem cells. In adults, it can cause encephalitis and myelitis due to infection of brain cells and Guillain–Barré syndrome later in the course of illness, a process thought to be immune-mediated.

Based on the results of the methacycline study and the fact that the drug has long been approved by the Food and Drug Administration, the senior author of the paper said that clinicians might consider prescribing it prophylactically for patients who intend to visit parts of South America in which Zika is now endemic.

“Women of childbearing age who are traveling to high-risk areas could take methacycline for the duration,” said Avindra Nath, MD, FAAN, chief of the section of infections of the nervous system and clinical director of the National Institute of Neurological Disorders and Stroke. “There's nothing to lose; there are few contraindications to giving the drug, particularly for short periods of time.”

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“Women of childbearing who are traveling to high-risk areas could take methacycline for the duration. Theres nothing to lose; there are few contraindications to giving the drug.”—DR. AVINDRA NATH

Neurologists and neuroscientists who specialize in neurovirology said they agree that methacycline could be given prophylactically to travelers, but expressed caution about prescribing it to pregnant women without evidence from randomized clinical trials. For now, they emphasized, non-pharmaceutical efforts are necessary to prevent all mosquito-borne viruses.

“You need to prevent not only Zika but dengue and chikungunya,” said Francisco Javier Carod Artal, MD, PhD, a tropical disease neurologist at Raigmore Hospital of the National Health Services Highlands in Inverness, Scotland. “If you are traveling in tropical regions, the first thing is to wear long sleeves, to use nets while sleeping, and to use mosquito repellant.”

For those living in areas where Zika is circulating, Dr. Carod Artal and others agreed, clinical trials are necessary to determine what role, if any, methacycline might have as a therapy. Ultimately, they said, vaccines (in addition to public health campaigns to control mosquito vectors) are necessary to control all the arboviruses.

Study Details

Dr. Nath's group set out to target the Zika's protease, a key enzyme that cleaves the viral protein into pieces small enough to be assembled for penetrating cell walls. Although other inhibitors of Zika protease have been developed in the past few years, most have problems that make them inappropriate for clinical treatment. One happens to be a red food coloring dye; another was found to be toxic in human neural stem cells.

To speed up their search for candidates, they screened thousands of compounds from a small-molecule library, as well as an artificial intelligence (AI) program that analyzed the structure and activity of another 137,083 compounds. The most promising candidates were then assayed for viral inhibition in a standard mammalian cell line, followed by testing in human neural stem cells with a Zika isolate known to cause microcephaly.

That process left them with eight compounds that effectively blocked Zika without apparent toxicity: methacycline, one of the earliest tetracyclines, and seven small molecules not previously tested in clinical trials. In a mouse model of Zika, methacycline reduced the extent of virus infection in their brains and improved motor deficits.

Two other investigational compounds had similar effects. The paper noted, “The extensive clinical data available for the use of tetracyclines would eliminate the need for a phase I safety trial in healthy adults, thus accelerating the path to efficacy trials.” Many tetracyclines have previously been shown to cross not only the blood-brain barrier but the placental barrier, “which would be necessary to treat a fetal infection,” the paper noted.

“Tetracyclines are relatively safe in pregnancy,” Dr. Nath said. “They do produce discoloration of the teeth, but when you're dealing with a disease like Zika, discoloration of the teeth is the least of your concerns.”

Teratogenic effects have not been linked to later-generation tetracyclines such as doxycycline, the paper noted. “Pending further investigation and a thorough discussion of the potential side effects with a medical professional, it is possible that the benefits of treatment with certain tetracyclines during pregnancy could outweigh the potential risks,” the study authors concluded.

In the absence of other treatment options, a clinical trial to test methacycline or other tetracyclines such as doxycycline or minocycline as an intervention for neurologic complications, such as Guillain-Barré syndrome, encephalitis, and myelitis, or as a prophylactic (to prevent infection and slow transmission) could be beneficial, the study authors wrote.

Expert Commentary

Carlos A. Pardo, MD, professor of neurology and pathology and director of the Johns Hopkins Transverse Myelitis and Myelopathy Center, said the study's AI analysis of potential therapeutics is a valuable new approach that should speed up the testing of future drug candidates. Even so, he said, “The only way to learn about the effects of these agents in humans is to test them in humans. That is where the problem will be.”

He agreed with Dr. Nath's view that methacycline could be administered prophylactically to people planning brief trips to areas of South America where Zika is still circulating at low levels. But, he added, “It will be extremely important to understand if methacycline is safe for use in pregnant women. I don't believe the safety profile has been fully clarified.”

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“The only way to learn about the effects of these agents in humans is to test them in humans. That is where the problem will be.”—DR. CARLOS A. PARDO

“It would be a good option for people visiting for a short period of time, a week or two, just as we give anti-malarial drugs prophylactically. But I don't think that long-term use of this medicine for people living in endemic areas would be practical or effective. We need a double-blind, randomized clinical trial.”

—DR. CAROD ARTAL

Using the drug as a treatment for an acute infection might also prove uncertain for some infection-related neurological problems, Dr. Pardo said. In the case of Guillain-Barré syndrome or forms of encephalitis, he said, “it shows up two to three weeks after the infection, due to immunological disturbances in the central and peripheral nervous system. Whether tetracyclines given during an acute infection will have any benefit on later immune reactions is unknown.”

A paper published last December in the journal Molecular Therapy found that the antiretroviral drug rilpivirine suppressed Zika viral infection and replication in primary human astrocytes and prevented Zika-induced death in a mouse model. The senior author of that paper said that a better approach to treating such infections might be to combine rilpivirine with methacycline.

“Combination therapy might be best,” said Kamel Khalili, PhD, the Laura H. Carnell Professor and chair of the department of neuroscience and director of the Center for Neurovirology at the Lewis Katz School of Medicine at Temple University.

For now, though, neurologists could consider prescribing a tetracycline to people planning a brief visit to countries in which Zika is now endemic, Dr. Khalili said.

“Combination therapy might be best.”

—DR. KAMEL KHALILI

Dr. Carod Artal agreed. “It would be a good option for people visiting for a short period of time, a week or two, just as we give anti-malarial drugs prophylactically,” he said. “But I don't think that long-term use of this medicine for people living in endemic areas would be practical or effective. We need a double-blind, randomized clinical trial.”

In October, Dr. Carod Artal coauthored an editorial in Lancet Neurology commenting on an observational study of neurologic complications in adults with Zika and chikungunya infections. Severe neurological complications requiring admission to an intensive care unit occurred in just two of 32 (6 percent) patients infected with just one of the viruses, compared with five of 14 (36 percent) infected with both viruses.

“We need to think of multiple viruses being transmitted by the same mosquito (Aedes aegypti; Aedes albopictus),” Dr. Carod Artal told Neurology Today. “During the Zika epidemic, there was evidence that people infected with more than one virus—dengue and Zika, chikungunya and Zika, or dengue and chikungunya—had more severe clinical features. That is why we need to control the vector, the mosquito. That is the first priority.”

Disclosures

Drs. Nath, Pardo, Carod Artal, and Khallili had no relevant disclosures.

Link Up for More Information

• Abrams RPM, Yasgarb A, Teramotoc T, et al. Therapeutic candidates for the Zika virus identified by a high-throughput screen for Zika protease inhibitors https://www.pnas.org/content/117/49/31365. Proc Natl Acad Sci USA 2020;117(49):31365–31375.
    • Carod Artal FJ, Araujo AQ-C. Neurological complications in adults with Zika and chikungunya virus infection https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(20)30309-4/fulltext. Lancet Neurol 2020;19(10):799–801.
      • Brito Ferreira ML, de Albuquerque MdFPM, Antunes de Brito CA, et al. Neurological disease in adults with Zika and chikungunya virus infection in Northeast Brazil: A prospective observational study https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(20)30232-5/fulltext. Lancet Neurol 2020;19(10):826–839.
        • Sariyer IK, Gordon J, Burdo TH, et al. Suppression of Zika virus infection in brain by the antiretroviral drug, rilpivirine https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(19)30460-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1525001619304605%3Fshowall%3Dtrue. Mol Ther 2019;27 (12):2067–2079.