Researchers at the University of Texas at Austin say that new work unravelling the molecular structure of a mitochondrial enzyme called polymerase gamma could allow future drug developers to identify new nucleoside analogues that are less toxic. Their work was published this week in Cell.
"Many anti-HIV drugs are designed to stop the process of DNA replication," says Dr Whitney Yin, assistant professor of chemistry and biochemistry. "That turns out to be a great thing to do to help cure virus infections, because it stop the processes of viral replication.
"At the same time, however, when you target such a critical process in viruses, you may also target human enzymes that perform similar functions in normal cells, and this is what causes harmful drug side-effects."
When mitochondria are working normally, they produce most of the energy that sustains human cells. When the polymerase gamma enzyme comes into contact with certain antiretroviral drugs, however, it can incorporate the drug into mitochondrial DNA, and thus interfere with the normal replication process. This interferes with the ability of mitochondria to function.
Of the antiretroviral drugs currently in use, d4T (stavudine, Zerit) and AZT (zidovudine, Retrovir) are most likely to be incorporated into polymerase gamma, leading to mitochondrial toxicities such as peripheral neuropathy (nerve damage), elevated lactate levels, neutropenia and myopathy (muscle damage).
Other antiretroviral drugs in the nucleoside or nucleotide analogue class such as 3TC (lamivudine, Epivir), abacavir (Ziagen) and tenofovir (Viread) have a much lower tendency to be incorporated into mitochondrial DNA, and do not cause mitochondrial toxicity. Their side-effects emerge due to other mechanisms.
"This is a unique opportunity for drug design," says Yin. "Now you have two pictures side by side. You have the viral target protein and the human protein. You know not to do anything in this region where the two proteins are similar, but rather focus in areas where they're different."
The discovery may also prove useful in redesigning existing drugs, such as d4T, to make them less toxic. D4T is very cheap to manufacture, due in part to the low dose of the drug that is given. A version tweaked to make it less toxic would be of particular interest in the developing world, but a major obstacle to a less toxic version of d4T is the need for significant investment in clinical trials in order to prove its safety and efficacy.
Adapted from a University of Texas press release.