Plotting the Perfect Protease Inhibitor
Symposium: Antiviral Drug Discovery
Dale Kempf. HIV Protease: Can Better Inhibitors Be Found? Thursday, 4:00 pm
Protease inhibitors (PIs) are potent anti-HIV drugs -- their arrival in 1995 was the main reason that AIDS death rates plummeted soon after. But PIs have their problems. If they don't send you running to the bathroom, they can cause one of your blood test values to soar or your kidneys to ache. Dale Kempf, of Abbott Laboratories, and one of the architects of Kaletra, discussed some new tools drug developers are now using to screen out these unwanted side effects before a new PI candidate ever gets into a human body.
The most obvious quality for any ideal HIV drug is potency. It should be able to quickly knock down viral load levels to the point where the virus is just barely replicating. Ideally, the drug should be able to do this not only for the virus that is most commonly found in the community (wild-type) but also for HIV that has become resistant to all other available drugs. And it should continue working even if a few new resistance mutations happen to crop up. These are all aspects that can be tested in the laboratory, and these are the qualities that drug designers look for first. In the old days, that was enough. But problems with existing PIs -- namely their side effects and their propensity to interact with the blood levels of other drugs -- keep us searching for the perfect PI.
The most attractive feature of the protease inhibitor Reyataz is that it doesn't cause the elevated blood lipid levels (cholesterol and triglycerides) that can come from using Kaletra. Unfortunately, this newer PI has its own quirky side effect that can make the eyeballs of some of its users turn yellow due to excess bilirubin in the blood. Kempf reports that scientists have been using new lab-based tools to understand the underlying mechanisms of these side effects so they can be avoided in future drugs.
New technology allows a drug to be tested against an array of tens of thousands of human genes all at once. Genes that become activated when exposed to the drug are targeted for further investigation. This was how Abbott scientists learned that Norvir, but not Reyataz, inhibits a cellular recycling system called the proteosome, which had been implicated in the lipid problem. Knowing this, Kempf and colleagues began looking for a potent PI molecule that didn't affect these proteosome genes. After several tries they found a promising candidate and continued tweaking it until it passed a similar test that looked for effects on bilirubin production. This finalist candidate was called A-792611 (at this early stage drugs have only numbers, not names) and it looked promising, with ten times the potency of lopinavir (the active PI in Kaletra) and little likelihood of sharing either Kaletra's or Reyataz's side effects.
At this point the drug scientists began assessing the potential for "611" (the compound's nick-number) to interact with other drugs. PIs are notorious for speeding up or slowing down each other's metabolism. While Norvir was originally developed as an antiviral drug, its true talent is in slowing down the elimination of other PIs. This "boosting" effect keeps PI blood concentrations higher, longer, which has made protease inhibitor therapy much more convenient and reliable than when it was first introduced. While "611" did not speed up the removal of other drugs, it stumbled when the assay revealed that it shuts down a key avenue of drug metabolism. Since this would have caused extreme and unmanageable drug interactions in real life, that was the end of the line for "611." Fortunately, all of this was discovered quickly and efficiently, and the molecular fiddling goes on to find the ideal PI candidate to take forward into human testing. Of course, surprises will always arise once a drug starts being used in people, but these new preclinical checkpoints should help increase the chances that the next PI down the pike is as easy on your body as it is tough on HIV.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.