At A Glance
Cytochrome P450 3A4 (CYP3A4) is a key metabolizing enzyme that regulates the body’s oxidation and clearance of most drugs. Inhibition of this enzyme improves the efficacy of drug cocktails and allows for the prescription of lower, less toxic doses of pharmaceutical drugs. UCI researchers, Dr. Irina Sevrioukova, Prof. Thomas Poulos, and Prof. Richard Chamberlin have developed new CYP3A4 inhibitors that are promising candidates for pharmacotherapy use.
• These CYP3A4 inhibitors can be co-administered with other pharmaceuticals to enhance therapeutic efficacy and decrease side effects.
• Pharmacophore modeling was utilized to design these compounds, resulting in highly specific binding and minimizing off-target effects.
• The new inhibitors are smaller and less complex than current on-the-market treatments, such as ritonavir and its variants.
• These new inhibitors have improved inhibitory concentrations relative to ritonavir.
Cytochrome P450 enzymes, including CYP3A4, play a vital role in the metabolism of pharmaceutical drugs. In some instances, these enzymes break down drugs too quickly, making treatments less effective. Thus, some drug cocktails include CYP inhibitors, which affords the active pharmaceuticals a longer lifetime in the body. Currently used CYP3A4 inhibitors, such as ritonavir (Norvir®), are highly active, but have undesirable, off-target effects.
The minimum and critical criteria required for ligand binding have been determined using models of the CYP3A4 enzyme. This method has 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. They differ from others in the primary binding moiety, which has been modified based on pharmacophore modeling.
Preliminary assessment of two novel inhibitors display inhibitory concentrations (IC50) less than ritonavir (IC50 = 0.52 and 0.13, respectively; compared to IC50 = 0.55 for ritonavir). The lower the IC50 value, the more effective the molecule is at preventing the undesired break down of the other pharmaceuticals in the drug treatment.
State of Development
Protein binding and inhibition studies have been completed. Future studies include animal studies and the synthesis of second generation inhibitors.
Patent Status: Patent pending.
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