Scientists design protein blockers to fight obesity and heart disease

According to US Centers for Disease Control and Prevention, nearly four out of ten American adults are obese. Even more alarming, in the last two decades alone, in states like Texas, residents' share of obesity has tripled. If nothing is done, obesity can even lead to more serious problems, including high blood pressure and fatal strokes.

To help reduce rising obesity rates, the University of Texas at San Antonio (UTSA) has received funding to use a new approach that inhibits the activity of a protein supposed to contribute to bad cholesterol.

Assistant Professor Francis Yoshimoto of the UTSA Department of Chemistry will design and test a protein blocker against the cytochrome P450 8B1 enzyme (P450 8B1). In previous research conducted by drug manufacturers, mice lacking the gene that expresses this protein are less likely to develop diabetes, heart disease, or stroke. They also resist weight gain.

"The scientific community has a hole in knowledge," said Yoshimoto. "We still have a lot to learn about the functions of P450 proteins."

Cytochrome P450 enzymes (P450 or CYP) are found in all living things, including plants. Humans have 57 P450 enzymes. The activity of the enzyme P450 8B1 is badociated with obesity.

In the past, Yoshimoto and his collaborators have discovered how the clbad of P450 enzymes metabolizes cholesterol, serves as a catalyst for the production of oxysterols (a clbad of hormones) and helps the human liver to treat medication. However, when these enzymes become hyperactive, they can alter the metabolic processes of the cell. A P450 can even produce estrogen, which promotes the growth of certain types of cancer.

Yoshimoto was inspired by previous studies at Merck. In these studies, transgenic mice lacking the gene encoding P450 8B1 were used and, despite their high fat diet, they still maintained lean weight.

The UTSA researcher then examined the current anti-cancer drug, abiraterone, a progesterone derivative that is used to reduce prostate cancer, and had a moment of eura.

Yoshimoto intends to use the same mechanism that the one used by abiraterone to stop P450 8B1. He thinks that the introduction of a pyridine into the backbone of the substrate will inhibit the active site of iron in P450 8B1.

He has a patent pending on his innovative approach.

"Nobody has been working on the P450 8B1 this way," Yoshimoto said. "The beauty of the design lies in the fact that it uses the same approach as an effective inhibitor of prostate cancer."

Yoshimoto's medicinal chemistry research is made possible through the Max and Minnie Tomerlin Voelcker Fund, which contributes $ 450,000 to the work. The Voelcker Fund supports promising medical research that can have a significant impact on patient care.

"The ultimate goal is to make a drug that fights obesity," Yoshimoto said.

This project is an example of UTSA's commitment to solving the world's most pressing health problems of society.

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