Drugs that target key enzymes in the life cycle of human immunodeficiency virus (HIV) have revolutionized the treatment of HIV in the past decade. Nevertheless, drug resistance remains a major problem. Writing in Chemistry and Biology, Schiffer and colleagues propose a novel structure-based strategy for combating drug resistance, using HIV-1 protease — for which several active-site inhibitors are approved — as an example.

HIV-1 protease cleaves the HIV Gag and Pol precursor proteins in at least nine different locations to allow viral maturation. It was originally speculated that this multiplicity of enzyme substrates would make the development of resistance to protease inhibitors unlikely, because the protease would be unable to accommodate mutations necessary to decrease the affinity of drug binding in its active site without seriously compromising its ability to bind at least one of its substrates. However, this has not turned out to be the case.

So, to understand how drug resistance can emerge while the protease retains its ability to recognise its substrates, the authors determined the crystal structures of an inactive variant of HIV-1 protease in complex with six of its known substrates. Using computational analysis to assess the overlap between the volumes in the active site occupied by these substrates, they identified an 'envelope' within the active site that apparently must be made available for substrate binding.

An analogous analysis with HIV-1 protease in complex with eight different inhibitors also revealed an envelope within the active site occupied by inhibitors. However, overlaying the 'inhibitor envelope' and the 'substrate envelope' revealed several regions where the inhibitor envelope protrudes beyond the substrate envelope. And crucially, many of the residues that have been reported to mutate in drug-resistant HIV-1 strains contact these regions.

It therefore seems that if future drug design focuses on developing inhibitors that interact strongly only with residues within the substrate envelope of HIV-1 protease, the chances of drug resistance developing would be reduced. Indeed, recent inhibitors indicate that this might be possible. Furthermore, this strategy could also be extended to other enzymes important in viral pathogenesis, such as the serine protease of hepatitis C virus.