October 7, 2002
Research on cells' 'power centers' sheds light on AIDS treatments
WEST LAFAYETTE, Ind. Companies that create HIV-AIDS drugs now have key information that could assist in making new medications with fewer side effects.
Researchers Henry Weiner, a professor of biochemistry at Purdue University, Steven Zollo of the National Institute of Standards and Technology and Lauren Wood of the National Cancer Institute, noted the similarity between HIV-AIDS treatment side effects and naturally occurring diseases. Certain HIV-AIDS treatment side effects, such as fat loss and insulin resistance, clinically resemble diseases of the mitochondria, the "power centers" in cells, that affect the functioning of other parts of the cell.
The researchers hypothesized that the drugs to combat HIV infection also might inadvertently affect the functioning of the mitochondria.
"Finding that a drug affects a different target than the one it was designed for is not unusual," said Weiner, an expert on protein processing in the mitochondria. The team speculated that current AIDS treatments using drugs that inhibit HIV proteins also could inhibit a key mitochondrial protein.
This speculation fits the observation by doctors that side effects resembling mitochondrial dysfunction originated after new drugs became part of the standard drug "cocktail" used to treat AIDS patients. Highly Active Antiretroviral Therapy, or HAART, has prolonged the lives of many, but also has been associated with side effects such as diabetes, high cholesterol and the development of fatty deposits.
To test the theory that the drugs were inhibiting the mitochondria, the researchers flooded isolated mitochondria with large amounts of the drugs and then measured the levels of processed protein in the mitochondria.
They found that a number of HIV-AIDS drugs can inhibit mitochondrial processing.
Although these findings suggest a possible link between HIV-AIDS drugs and mitochondrial dysfunction, Weiner said he believes that investigating the mitochondria of patients in treatment, or using tissue culture grown in the lab, is the next step.
"That is the only way to determine whether actual patients taking the medication are more than just slightly compromised by the effects of the HIV-AIDS medication on their mitochondria."
In the interim, Weiner said drug companies may find this information useful in efforts to make medications with fewer side effects.
"Drug companies making new AIDS protease inhibitors can take the enzyme we used and screen new potential drugs and select ones that can fight the virus but not damage the mitochondria," he said.
Drug manufacturers may not have made the connection to the mitochondria because the drugs' effects are minor, Weiner said.
"The protease inhibitors were weak inhibitors of the mitochondria's enzymatic processing system," he said. "If they were better inhibitors, that would have likely led to more serious complications in patients."
Weiner also sees other possible impacts from the research, such as potential anticancer treatments. He said scientists might find a "good way to kill tumors," by inhibiting specific enzymes within the tumors' own mitochondria.
The research was published in the September issue of the Journal Mitochondrion. Weiner's portion of the research was funded in part by the National Institutes of Health.
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