Drug blocks Zika and other deadly viruses in cells cultures, Stanford study finds

Photo of Jan Carette by Paul Sakuma

A team of Stanford researchers is developing approaches to thwart a family of deadly viruses, called flaviviruses, by targeting the human cells that host these invading pathogens.

Flaviviruses include the dengue-fever, yellow-fever, West Nile and Zika viruses transmitted to humans by mosquitoes, as well as encephalitis transmitted by ticks. Unfortunately, approved antiviral drugs for these diseases aren’t currently available.

So, instead of the traditional approach of attacking an individual virus directly, the researchers focused on the cellular factors of their human hosts that are essential to many viral infections.

“Generally, when you develop a drug against a specific protein in dengue virus, for instance, it won’t work for yellow fever or Zika, and you have to develop new antivirals for each,” said Stanford virologist Jan Carette, PhD, in a recent Stanford news release. “Here, by targeting the host rather than a specific virus, we’ve been able to take out multiple viruses at once.”

Earlier, the team genetically profiled human cells to identity the host factors necessary for the viruses to replicate inside the cells — revealing new candidate targets for antiviral drug development. Specifically, they demonstrated the importance of the oligosaccharyltransferase (OST) complex that attaches sugar molecules to proteins. They found flaviviruses did not infect their genetically engineered cells without OST.

In the new study, recently published in Cell Reports, the Stanford researchers collaborated with scientists at Yale University to test the effectiveness of a drug called NGI-1, which inhibits the activity of the OST complex.

They showed that low concentrations of NGI-1 could be used to block the viruses from replicating without harming the host cells — successfully reducing the infection by 99 percent when treating cells immediately after they were infected by Zika or dengue virus, and by 80 percent when administered 24 hours after infection.

Their study also indicated that the viruses are unlikely to become resistant to NGI-1. “When you target a host function rather than a viral protein, it’s usually much more difficult for a virus to develop resistance,” Carette said in the release.

The researchers are now busy with follow-up studies to test NGI-1 in small animal models of dengue fever and are also developing similar drugs with improved specificity.

This is a reposing of my Scope blog story, courtesy of Stanford School of Medicine.

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To battle mosquito-borne disease, SLAC x-ray laser provides new view of insecticides

Illustration, of LCLS x-ray pulses blasting BinAB nanocrystals composed of protein BinA (yellow) and BinB (blue), courtesy of SLAC National Accelerator Laboratory.
Illustration of LCLS x-ray pulses blasting BinAB nanocrystals composed of protein BinA (yellow) and BinB (blue), courtesy of SLAC National Accelerator Laboratory.

Mosquitoes continue to spread devastating diseases such as malaria, West Nile virus, dengue fever and Zika virus throughout the world. Sadly, there are no medications or vaccines for many of these deadly diseases, so it’s critical to prevent mosquito bites.

A cost effective way to eliminate these disease-bearing insects is the use of specialized insecticides that target against the larval stage of a mosquito. These larvicides, like BinAB, kill some mosquito species, but they are currently ineffective against Aedes mosquitoes that transmit Zika and dengue fever. Now, an international team of researchers is working to develop a new toxin that will kill a broader range of mosquito species, including Aedes.

The existing larvicide BinAB is composed of two proteins, BinA and BinB, which pair together to form nanocrystals inside Lysinibacillus sphaericus soil bacteria. When these bacteria are distributed on the surface of stagnant water locations where mosquitoes breed, the mosquito larvae eat the bacteria — dissolving the nanocrystals that bind to their gut, activating the deadly BinAB toxin and killing the larvae.

The proteins are toxic to the mosquitoes, but harmless to humans and other animals. Unfortunately, previous research has shown that BinAB is also harmless to an Aedes mosquito, because the protein never binds to the insect’s gut so the toxin isn’t activated.

“Part of the appeal is that the larvicide’s safe because it’s so specific, but that’s also part of its limitation,” said Michael Sawaya, PhD, a scientist at the UCLA-DOE Molecular Biology Institute, in a recent news release.

Now, the researchers are adapting the BinAB toxin to attack mosquito species that are insecticide resistant. In order to do this, they needed to understand the 3-D structure of the BinAB proteins and how they work. This was a challenge, because the nanocrystals were so tiny and their structural details were a mystery.

The research team increased the size of the nanocrystals using genetic engineering, and then blasted them with an intense beam of bright, fast pulses of light using the Linac Coherent Light Source (LCLS) at the SLAC National Accelerator Laboratory. This allowed the team to collect detailed structural data from the tiny crystals and create 3-D maps of the electron density of the BinAB protein, as reported in a recent paper in Nature.

The LCLS experiments helped the researchers fully understand how the BinAB protein forms and functions. They are now engineering a modified version of the protein that will kill a broader range of mosquito species.

“The most immediate need is to now expand the spectrum of action of the BinAB toxin to counter the progression of Zika, in particular,” said Jacques-Philippe Colletier, PhD, a scientist at the Institut de Biologie Structurale in France, in the news release. “BinAB is already effective against Culex [carrier of West Nile encephalitis] and Anopheles [carrier of malaria] tos. With the results of the study, we now feel more confident that we can design the protein to target Aedes mosquitoes.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.