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Dimerised drug leads two pronged attack on HIV

2011-09-19

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Jean Chmielewski

Reservoirs of HIV in the brains of infected people pose a real problem, as they are difficult to eradicate. A new strategy employing antiviral drug dimers might lead to a way to get the drugs into the brain and tackle this viral reservoir.

Unlike the virus itself, few antiretroviral drugs can cross the blood-brain barrier (BBB), making it difficult to target the virus. Now, Jean Chmielewski and Christine Hrycyna at Purdue University, US, and colleagues have targeted P-glycoprotein (P-gp), a transporter protein that is highly expressed in the BBB, and prevents many small molecules from entering the brain. "A number of HIV therapies, especially the protease inhibitors and a few reverse transcriptase inhibitors, are substrates of P-gp," explains Chmielewski. "P-gp is known to have at least two binding sites, and so we investigated whether dimerising the small molecule drug would increase its binding affinity for P-gp, and turn the substrate-drug into an inhibitor."


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Christine Hrycyna

They joined two molecules of the reverse transcriptase inhibitor abacavir to make a dimer. The tether between the two molecules included a disulfide link, so that if the dimer reached the reducing environment of a cell the drug would be released. This provides a two-pronged approach to the problem - it inhibits the pump that prevents drugs crossing the BBB and delivers the drug to the brain.

Source: Royal Society of Chemistry - Chemistry World

Related link:American Chemical Society C&EN article

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