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Researchers target drug-resistant strains of HIV

by Paul Karon
The research team showed how it’s possible to generate new inhibitors of integrase, a promising target for HIV drug development.
The research team showed how it’s possible to generate new inhibitors of integrase, a promising target for HIV drug development.

USC researchers have demonstrated a way to generate potential new drugs to halt the replication of HIV in infected patients by inhibiting a crucial enzyme in the virus’ reproductive cycle.

The research team, led by Kyung Jung, associate professor at the Loker Hydrocarbon Research Institute and the Department of Chemistry at the USC Dornsife College of Letters, Arts and Sciences, showed how it’s possible to generate new inhibitors of integrase, a promising target for HIV drug development, by altering a molecule called the pyrazolone scaffold.

“By manipulating the pyrazolone molecule in various ways, we were able to develop and test promising new agents,” Jung said. “We discovered new chemical entities that were effective in the inhibition of the integrase.”

AIDS affects nearly 40 million people worldwide. Since its detection in 1981, more than 25 million people have died of the disease, making it the fourth-largest cause of death globally, according to the World Health Organization.

Medicine’s battle against AIDS leapt forward in 1996 with the introduction of antiretroviral drugs that suppressed the replication of the virus in the body by interfering with the function of HIV enzymes.

New medicines, however, are critically needed because HIV mutates quickly into drug-resistant strains, rendering older medicines ineffective.

Currently, a cocktail of three drugs is considered the best therapy for HIV patients. It has enabled millions with HIV to thrive for years in relatively good health, halting or slowing what had once been a nearly inevitable progression that leads to the collapse of the immune system and the onset of fatal opportunistic infections and diseases.

More than 20 drugs have been approved by the U.S. Food and Drug Administration (FDA) to treat HIV/AIDS. Two drugs have been developed to inhibit integrase, one of which has received FDA approval. But, like other HIV drugs, those initial integrase inhibitors can also be expected to lose their effectiveness.

“Once the first generation of integrase inhibitors becomes commonly used in the clinic, the emergence of resistant HIV virus strains is inevitable,” Jung said. “That’s why a second generation is so urgently needed.”

The project was supported by a Southern California Clinical and Translational Science Institute (SC STSI) pilot-funding program designed to accelerate the translation of basic research into real-world applications. The program supports specific career development efforts in translational science, as well as all phases of translational research, from preclinical studies to community-partnered projects that further research goals while delivering needed clinical or community health solutions.

The research team also uncovered APE1, a new target against HIV that could also lead to novel medicines. As a result, investigators filed a provisional patent based on their work.

The team’s findings were published in Bioorganic & Medicinal Chemistry Letters.

Researchers currently are seeking additional support to continue their search for potential new HIV/AIDS drugs.

SC CTSI and Childrens Hospital Los Angeles is part of the 60-member Clinical and Translational Science Awards network funded through the National Center for Advancing Translational Sciences at the National Institutes of Health (grant number UL1TR000130).

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