MU researchers aim to improve HIV drugs

Bond Life Sciences Center researchers are working to identify weak spots in the HIV virus.

In order to figure out the role of a key protein in the HIV virus’s life cycle, researchers at the Bond Life Sciences Center are exploring the protein’s structure.

HIV, or human immunodeficiency virus, is a virus that attacks the immune system, leading to AIDS. There are currently about 35 million people living with HIV, and although combination drug therapies help improve quality of life for patients, they eventually end up developing resistance to these drugs, and the drugs become ineffective. Therefore, it’s important to researchers to understand how drug resistance develops and also to discover and develop new drugs to help improve antiviral therapies for those infected by HIV.

Karen Kirby, a research scientist on the protein study, and Stefan Sarafianos, the lead author of the study, came across some inhibitors while screening for new drugs to treat HIV. The protein that the researchers found became a building block that formed the virus’ capsid, a protein shell that encloses the genetic material of a virus.

In order to understand how the molecule was binding to the HIV capsid, they studied the structure using X-ray crystallography to derive the atomic structure of the proteins and see how the crystals interacted with the drugs. X-ray crystallography is a tool used for identifying the atomic and molecular structure of a crystal, in which the crystalline atoms cause a beam of incident X-rays to diffract into many specific directions.

“(Researchers) took many copies of the protein and coaxed them into forming a patterned, crystalline lattice,” Caleb O’Brien wrote in a post on the Bond Life Sciences Center’s website. “Next, they shot high-powered X-ray beams at the crystal. By interpreting how the X-rays scattered when they ricocheted off the proteins, the researchers made a 3-D map of the protein.”

The researchers had to test their 3-D structure of the protein until it matched the map produced by the X-ray diffraction pattern. Creating the protein crystals in the first place was a challenge, Kirby said, because of the many variables such as salts and additives in the liquid to the amount of protein in the mixture. Because of that, it is difficult to foresee which solution will grow crystals – it is essentially a guessing game.

“The real challenge begins afterwards, as one needs to manually optimize the initial crystallization conditions to find the one that will produce protein crystals of desired quality,” said Anna Gres, a graduate student who led the study, in the post. “This process can take years. In our case, I think we were lucky: It took approximately 500 manual screenings and about six months.”

Lucky for them, the crystals formed in groups of six proteins, which matched their capsid. Gres said she still has no idea what fine details made the difference in order for the crystals to match the 3-D model.

After researching the effect of the interaction between hexamers and the capsid, researchers found that dehydrated crystals resulted in a change in the crystal’s shape. Because of this change in shape due to the water molecules, the capsid’s “malleability and plasticity could be critical to the life cycle of the virus and allow it to act as a multi-functional molecular Swiss army knife,” Sarafianos said in the post.

With a clearer image of the capsid protein, future research looks promising for scientists. The results provide insight into the larger picture and give researchers an idea of how the virus potentially forms this capsid shell and protects the viral contents inside the virus particle. They hope to continue to study interactions with potential new drugs.

This capsid is a new target that can produce potential new drug development and enhance current therapies for patients, Kirby said. Overall, the researchers’ goal is to be able to produce new and effective antiviral drugs with the testing and refining of these molecules.

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