Cytochrome P450 3A4 (CYP3A4) is a key metabolizing enzyme that regulates the oxidation and clearance of most drugs. The inhibition of this enzyme may be useful in improving the efficacy of drug cocktails and the ability to give lower, less toxic doses of drugs. The development of new CYP3A4 inhibitors with high affinity and specificity is described.
Cytochrome P450 enzymes, including CYP3A4, play a vital role in the metabolism of pharmaceutical drugs. In some instances, these enzymes breakdown drugs too quickly, making treatments less effective. Thusly, some drug cocktails include CYP inhibitors, which affords longer lifetimes in the body of the other active components. Currently used CYP3A4 inhibitors, such as Ritonavir (trade name Norvir), are highly active, but have undesirable, off-target effects.
Using models of the CYP3A4 enzyme, the minimum and critical criteria for ligand binding have been determined. This method yielded novel inhibitors that may have better efficacy and/or less off target effects than current treatments. Like most CYP inhibitors, these molecules are short amino acid-like sequences. Preliminary assessment of two of the most promising designed inhibitors have inhibitory concentrations less than ritonavir (IC50 = 0.52 and 0.13, respectively; compared to IC50 = 0.55 for ritonavir).
Protein binding and inhibition studies have been completed. Future studies include animal studies and utilizing these compounds for the synthesis of second generation inhibitors.
Cytochrome P450, CYP3A4 inhibitor