Researchers use protein-to-protein interaction between viruses and human cells to narrow down on potential treatment targets
Two papers published on the same day identified how the Ebola, dengue, Zika viruses hijack and interact with the human body, while suggesting potential treatments.
The studies were published in the December 13, 2018, issue of journal Cell, led by Georgia State University, the University of California, San Francisco (UCSF) and the Gladstone Institutes. It used protein-to-protein interaction between viruses and human cells to narrow down on potential treatment targets. The first study identified 194 virus-human interactions involving six Ebola proteins. It narrowed down to one specific point of contact between Ebola protein VP30 and human protein RBBP6.
The protein RBBP6 prevents VP30 and another Ebola virus protein NP from interacting—crucial for the virus to replicate—by attaching to VP30 itself. This finding revealed how the human body protects itself against the virus, and gives way to potential drugs that can mimic the effects of RBBP6 to fight off Ebola infection.
“We often find viral proteins that have evolved to mimic human proteins, but here it’s the opposite. It appears our body has a natural way to fight off Ebola infection, and the virus hasn’t gotten around it. Keep in mind, we still don’t have great mechanisms to fight off Ebola, but without this protection the virus would be even deadlier,” says Jyoti Batra, PhD, one of the authors of the paper.
In the second paper, the scientists looked at the dengue and Zika viruses—both transmitted through mosquitos and cause similar clinical symptoms. They mapped interactions between the Dengue virus and mosquito proteins to compare it to the human–virus protein maps. Subsequently they found one interaction that occurred in both viruses and both host species— the viral protein NS4A and the host protein SEC61. SEC61 has previously been associated with some forms of cancer, and when compounds targeting these proteins were added to the human and mosquito cells, they effectively wiped out both the dengue and Zika infections.
“We’ve employed our systematic protein–protein interaction strategy on Ebola, dengue, and Zika to get a better sense of how these three very problematic viruses hijack, rewire and infect human cells. To me, what’s most interesting is when we see the same human machinery being hijacked by seemingly very different viruses and different pathogenic proteins,” says the leader of the two studies, Nevan Krogan, PhD, and professor of cellular and molecular pharmacology at UCSF.
Further, the scientists looked into how the Zika virus causes the birth defect microcephaly. The fact that dengue and Zika are very similar, but only Zika virus causes the condition, helped scientists narrow down on Zika proteins which interacted with human proteins, while Dengue proteins did not. They found that the Zika protein NS4A appeared to inhibit the function of human protein ANKLE2, which is important for brain development. This finding can help develop a drug or method to target ANKLE2 and prevent Zika-related microcephaly.
The two studies, conducted under the umbrella of the Host Pathogen Mapping Initiative launched by the Quantitative Biosciences Institute (QBI) at UCSF, have paved a way for developing new treatments for Ebola, dengue and Zika, or restructuring existing ones. By targeting protein interactions identified in the two studies—especially the human proteins RBBP6 and SEC61—the researchers were able to eradicate (in the lab) all three viruses from human cells.
“We’re starting to see there’s overlap among the proteins hijacked by different viruses. These same proteins are often mutated in diseases with genetic roots, like cancer and autism. The more commonalities we can find between seemingly unrelated diseases, the better we can identify therapies to treat these devastating conditions,” said Krogan.
Currently, there are no drugs available to treat Ebola, Dengue and Zika diseases. The Ebola virus, which was first reported in 1976, bleeds 50 per cent of its victims to death. The disease has resurfaced in the conflict-ridden Democratic Republic of the Congo (DRC), while its worse outbreak occurred in West Africa between 2013 and 2016, causing about 28,000 infections and 11,000 deaths.
Zika, a zoonotic disease, was declared a public health emergency of international concern in February, 2016. It was first isolated from the rhesus monkey in Uganda’s Zika forest in 1947 and in humans in 1952, but in 2007, there was a massive outbreak. And dengue has continued to remain a huge cause of concern for health authorities in India, especially in Delhi.
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