Exploiting Drug Repositioning for Discovery of a Novel HIV Combination Therapy
Christine L. Clouser,1,2 Steven E. Patterson,3 and Louis M. Mansky1,2,3,4*
Institute for Molecular Virology,1 Department of Diagnostic and Biological Sciences, School of Dentistry,2 Center for Drug Design,3 Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota 554554
Received 8 May 2010/ Accepted 29 June 2010
The development of HIV drugs is an expensive and a lengthy process. In this study, we used drug repositioning, a process whereby a drug approved to treat one condition is used to treat a different condition, to identify clinically approved drugs that have anti-HIV activity. The data presented here show that a combination of two clinically approved drugs, decitabine and gemcitabine, reduced HIV infectivity by 73% at concentrations that had minimal antiviral activity when used individually. Decreased infectivity coincided with a significant increase in mutation frequency and a shift in the HIV mutation spectrum. These results indicate that an increased mutational load is the primary antiviral mechanism for inhibiting the generation of infectious progeny virus from provirus. Similar results were seen when decitabine was used in combination with another ribonucleotide reductase inhibitor. Our results suggest that HIV infectivity can be decreased by combining a nucleoside analog that forms noncanonical base pairs with certain ribonucleotide reductase inhibitors. Such drug combinations are relevant since members of these drug classes are used clinically. Our observations support a model in which increased mutation frequency decreases infectivity through lethal mutagenesis.
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* Corresponding author. Mailing address: Institute for Molecular Virology, University of Minnesota, 18-242 Moos Tower, 515 Delaware St. S.E., Minneapolis, MN 55455. Phone: (612) 626-5525. Fax: (612) 626-5515. E-mail: [email protected]
JVI: 两种用于癌症治疗的药物可抑制HIV2010年08月21日 星期六 04:34Researchers at the University of Minnesota Academic Health Center have identified two drugs that, when combined, may serve as an effective treatment for HIV.
The two drugs, decitabine and gemcitabine -- both FDA approved and currently used in pre-cancer and cancer therapy -- were found to eliminate HIV infection in the mouse model by causing the virus to mutate itself to death -- an outcome researchers dubbed "lethal mutagenesis."
This is a landmark finding in HIV research because it is the first time this novel approach has been used to attack the deadly virus without causing toxic side effects. Because decitabine and gemcitabine are already FDA approved, researchers believe that if their research is effective in large animal models, it will be much easier to expedite the development of the drugs for human use.
The study is a collaboration between molecular virologists Louis Mansky, Ph.D., and Christine Clouser, Ph.D., of the Institute for Molecular Virology and School of Dentistry, as well as medicinal chemist Steven Patterson, Ph.D., from the Center for Drug Design. The findings were recently published online in the Journal of Virology.
"The findings provide hope that such an approach will someday help the 33 million people worldwide who currently live with HIV," Mansky said.
Lethal mutagenesis
HIV mutates and evolves quickly. Rather than inhibiting virus growth and replication like current HIV drugs, this new drug combination forces the virus to do just the opposite -- evolve beyond control, to the point of extinction.
"HIV's ability to mutate makes it difficult to target and treat," Mansky said. "We wanted to take advantage of this behavior by stimulating HIV's mutation rate, essentially using the virus as a weapon against itself."
Drug repositioning
One way to decrease cost and expedite the development of novel drugs is by the use of drug repositioning, the process of taking a drug that is used to treat one medical condition, and using it to treat a different illness.
By examining drugs that are already approved by the Food and Drug Administration, the researchers hope to expedite the development of this drug combination because the safety profiles of the two drugs are known.
U of M researchers found that the drug concentrations needed to eliminate HIV infection cause no measureable cell toxicity and were effective against HIV cultures at concentrations well below the current levels used for cancer treatment.
The path ahead
Gemcitabine and decitabine have been administered in pre-clinical trials with mice. Initial findings confirm that the drugs are an effective antiviral therapy for HIV.
The researchers are now in the process of modifying the drugs to forms that can be absorbed by the human body when taken orally.
