HIV drug dimer can both cross into the brain and inhibit protein pump that expels it

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.’ 

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: © J. Am. Chem. Soc.

The antiviral drug dimer can enter the brain and then separate to attack HIV

As well as cell-based assays, the team has used an in vitro BBB model using rat brain capillaries. This enabled them to see whether P-gp is inhibited in the capillaries themselves, and they found that it is. ’We have also shown, with David Davis at NIH [National Institutes of Health, US], that the reductive strategy to regenerate the therapy works inside HIV-infected T-cells,’ she says. ’The dimeric abacavir does not have any antiretroviral activity, and it is only active after it has rearranged to give back the monomeric therapy.’ 

According to Tony Wood, head of medicinal chemistry at Pfizer, this represents an imaginative approach where dimerisation of a P-gp substrate is used to create an inhibitor of the pump that limits central nervous system penetration. ’It is an intriguing observation, and it will be interesting to see how general the approach may be,’ he says. ’Many HIV treatments are large, polar molecules that have low intrinsic permeability, so its usefulness will depend on the balance between permeability and P-gp efflux for any given compound.’ 

The next step will be to carry out perfusion experiments to see if there is enhanced brain penetration in vivo. ’We have already studied another dimerised substrate of P-gp, and found inhibition of P-gp in vivo,’ Chmielewski says. ’We are feeling pretty confident that dimerised abacavir should also work in animals.’ 

Sarah Houlton