Substrate-Envelope-Guided Design of Drugs with a High Barrier to the Evolution of Resistance

Abstract

Drug resistance is a major problem in quickly evolving diseases. One way for drug resistance to emerge is through mutations in the drug target under the selective pressure of therapy. Antiviral drug targets especially have a high mutational plasticity due to the diverse genetic viral population. An ideal antiviral inhibitor should be robust against these quasispecies. Fortunately, a therapeutic target can be evolutionarily constrained by the biological function, which limits the mutational space. Taking advantage of this evolutionary constraint, the substrate-envelope hypothesis quantitatively defines the balance between natural substrate recognition and inhibitor binding and provides a framework to design robust inhibitors that retain potency against mutational ensemble of quasispecies of the target. The Substrate envelope hypothesis, based on structural studies on the proteases of HIV-1 and hepatitis C, provides a structural basis for the specificity of natural substrate recognition and mechanisms for the resistance mutations in the active site.