A study of the structure of an HIV enzyme may further explain why resistance can arise to a common class of HIV drugs called protease inhibitors. The work could help researchers design better drugs to which HIV would struggle to develop resistance.
HIV protease inhibitor drugs slow HIV by blocking the HIV protease enzyme. This enzyme is crucial in the last stage of viral replication within human cells. It binds to a substrate 鈥� its target protein 鈥� and cuts it up to use the pieces to build more of the infectious virus.
When the protease inhibitor is present, the enzyme binds to it instead, leaving the substrate in one piece. 鈥淏y blocking the scissors the virus can鈥檛 become infectious,鈥� explains Schiffer.
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The enzyme has been a target of some of the most successful HIV drugs for almost 10 years. 鈥淧rotease inhibitors have turned the lives of many people around,鈥� says Celia Schiffer of the University of Massachusetts Medical School and one of the authors.
Win-win situation
It was originally thought that if HIV mutated to prevent the drug from binding it would also prevent binding to a substrate, making it a win-win situation for the drug designers: either no resistance is developed, or the virus kills itself.
But HIV is hard to pin down, and its swift rate of mutation has led to resistance. 鈥淗IV is tireless,鈥� says Edward Arnold of Rutgers University, New Jersey, US. 鈥淚t鈥檚 a moving target so you have to understand the movement and target it or understand the conserved portions of enzyme. You usually try to do both.鈥�
Schiffer and her colleagues were able to crystallise most the enzyme鈥檚 target substrates and compare their shape with eight drugs that compete to bind to HIV protease. The shape of the substrates is important as it allows it to fit into a 鈥渂inding site鈥� on an enzyme, which then allows the enzyme to work.
The results explained the resistance. 鈥淚f you superimpose the substrate鈥檚 binding with the inhibitor鈥檚 binding some parts protrude beyond where the substrates are,鈥� says Schiffer.
Viral evolution
She says these areas of protrusion are more important for the drug to bind than they are for a substrate to bind. Consequently if the protease enzyme of the virus mutates in these areas it would be able to carry out its job unaffected by the drug. 鈥淚f it can evolve to become resistant to the drug, it will do so,鈥� says Schiffer.
A similar approach carried out by Arnold and his colleagues predicted that drugs targeting another essential enzyme of HIV, reverse transcriptase, would be more effective if they were made smaller so as not to protrude beyond the substrate profile. When a drug was later made that fitted this criterion, it was indeed more effective. 鈥淭his kind of concept can aid drug design,鈥� says Arnold.
Schiffer鈥檚 work could help drug development keep pace with the ever-changing virus. 鈥淲hen they were designing the drug they didn鈥檛 pay as much attention to the details of how the substrate is bound,鈥� she explains. The emphasis was all placed on inhibiting the enzyme, which was not enough to keep HIV in check for long. 鈥淲hatever you鈥檙e targeting, inhibition is necessary, but not sufficient for a robust drug,鈥� says Schiffer.
Journal reference: Chemistry & Biology (DOI: 10.1016/j.chembiol.2004.08.010)
