Mutations and the loss of water molecules help an important enzyme of the human immunodeficiency virus escape from the binding effect of drugs.
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Researchers at the Francis Crick Institute of Cancer in London and the Dan-Farber Cancer Institute in Boston have described the mechanism by which human immunodeficiency virus can develop resistance to commonly used drugs. An article about this work is published in the journal. Science.
Today, there are a number of drugs that help control HIV infection. Including these drugs are viral integrase inhibitor preparations: raltegravir, elvitegravir, dolutegravir and bitegravir. All of them bind to one of the key HIV enzymes, blocking the incorporation of viral DNA into human chromosomes.
Although integrase inhibitors are highly active in binding and blocking the enzyme, over time, the virus can weaken the connection between the enzyme and the drug molecule. Scientists have discovered this in the process of studying viral integrase by cryoelectron microscopy.
“The unusual property of these drugs is that they interact with metal ions (for example, zinc in the case of integrase. – Ed.), Which usually allows them to create very strong bonds with the active center of the viral enzyme,” explains Peter Cherepanov, one from the co-authors of the study. “We found that HIV can subtly alter the chemical environment of metals and, as if through remote control, weaken the degree of binding.” The decrease in the binding effect of the drugs is due to the combined effect of mutations and the loss of water molecules in the active center of integrase.
The study allowed scientists not only to establish how the enzyme is exempted from “drug bonds”, but also to clearly visualize the area of drug binding to integrase. “It will be the basis for the development of more effective integrase inhibitors that could improve the lives of many millions of people living with HIV, ”said Alan Engelman, another co-author of the work.
The work carried out by Cherepanov, Engelman and their colleagues is important for understanding the mechanisms for developing resistance to a whole group of “first-line” antiviral drugs. In addition, the study shows the potential of cryoelectronic microscopy to detect complex intermolecular bonds.
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