The key viral structures shows how HIV drugs work at the atomic level, Salk scientists have discovered how a class of powerful HIV drugs binds important parts of the HIV machine.
For the first time, researchers completed this complex three-dimensional structure while applying various drugs and showing what makes this therapy so powerful.
The drugs we have learned are the latest compounds available at the clinic today, as well as some important preclinical molecules. So far, no one knows exactly how to deal with this HIV complex, researchers say. A better understanding of how drugs work helps us to improve them and develop new therapeutic compounds. The key viral structures shows how HIV drugs work at the atomic level.
Intasome is a critical structure of the virus that allows infection consisting of HIV protein integrase and the DNA strand of the virus that is formed when the virus attacks human cells.
Intasomes move into every human cell and are then subject to the chemical reactions needed to integrate the genetic material of the virus into human DNA.
Some drugs called INSTI inhibitors (Integrase Transfer Inhibitors) have blocked intasomes. HIV cannot infect human cells if the complex cannot integrate viral DNA into the human genome.
Four INSTIs from the US Food and Drug Administration and others are under development.
Apart from the success of these molecules, researchers have difficulty learning how they inhibit the intasome of HIV, mainly because of the difficulty in isolating the intasome for structural studies.
The team used single-particle oblique cryo-electron microscopy (cryo-EM), an imaging technique that has been used to optimize the structure of each intasomal drug complex.
The first observation made by researchers was how different drugs that are bound to the HIV intasome from those seen with the PFV intasome.
For example, the compound known as 4f returns to itself when it binds to the PFV intasome, but remains relatively flat because it binds to the HIV version of the complex. These details can help researchers improve the binding properties of potential molecules in the future. The key viral structures shows how HIV drugs work at the atomic level.
Until now, everyone used the PFV intestine to rationalize and understand the mechanism of action of this drug, the researchers said.
“We and many others have worked to achieve this goal for decades, and it is very exciting that we can now finally understand the workings of HIV inhibitors in detail and support the development of new drugs,” the researchers said.
The structure also shows why drugs are very powerful and what makes them very good at avoiding drug resistance. The INSTI discovered by Lyumkis and his colleagues filled the entire space normally occupied by DNA.
This means that if HIV intase develops mutations that inhibit the binding of INSTI drugs, it will also block DNA binding, making complexes that cannot be used for human cell invasion.
The very high resolution of the structure obtained from the Salk researchers finally allowed them to see details about how the drugs interact chemically with this binding bag and how INSTI moves water molecules to give the team even more information. That is what made INSTI so successful in the clinic. The key viral structures shows how HIV drugs work at the atomic level.
Researchers are planning additional work on experimental drugs that will focus on a compound known as 4d. This is based on preclinical tests and new structural concepts and is more promising about HIV than other compounds.
They also want to better understand what happens to intasome structures if they develop resistance to INSTI, the researchers said. This can help them develop more effective medicines in the future.