Combating Drug Resistance: The balance between inhibition and substrate processing

Resistance is a major problem in the development of robust new therapeutics to quickly evolving diseases. Viral proteases, critical to maturation, are effective targets for antiviral therapy. However, when the virus evolves, resistance quickly emerges. In solving the crystal structures of HIV‐1 protease substrate complexes, we developed the substrate envelope hypothesis and designed potent inhibitors that are less susceptible to drug resistance by staying within the substrate envelope. Yet, we have recently discovered that changes in HIV Gag also confer PI resistance in a PI specific manner. These results reinforce the complexity that resistance occurs as the balance of substrate recognition/processing and inhibitor binding are perturbed. Resistance is also emerging quickly to inhibitors are being developed for another viral protease, Hepatitis C NS3/4A. Once again, crystal structures of product complexes verify that most of resistance mutations are occurring outside of the HCV substrate envelope. Suggesting that the substrate envelope constraint should also be applied to development of HCV inhibitors to make them less susceptible to resistance. Understanding the molecular basis for substrate recognition is critical to develop effective inhibitors that avoid resistance against quickly evolving enzymatic targets.