Despite being responsible for breaking down over 80% of FDA-approved drugs, controlling the negative impacts of Cytochrome P450 (CYP) proteins without off-target effects has puzzled scientists until now.
Published in Nature Communications, recent research by St. Jude Children's Research Hospital scientists has resulted in a novel drug framework which selectively targets one of CYPs most critical proteins, offering a new path for drug interaction evaluations and CYP protein targeting.
CYP3A4 is one of the most critical CYP proteins and is responsible for breaking down drugs used to treat various health conditions. To combat this, CYP3A4 inhibitors are regularly co-administered. However, this co-administration of CYP3A4 inhibitors often effects CYP3A5 due to their shared features. Unintended inhibition of CYP3A5 or other CYPs can have drastic effects if not accounted for.
"When a nonselective CYP3A inhibitor is used to maintain the efficacy of a CYP3A4-metabolized drug, the unnecessary inhibition of other CYPs will lead to dangerously elevated plasma levels of drugs metabolized by the unintended CYPs," said Taosheng Chen, Ph.D., PMP, St. Jude Department of Chemical Biology & Therapeutics.
To understand the mechanism behind CYP selectivity the team utilized X-ray crystallography to conduct a structural comparison between CYP3A4 and CYP3A5. The results of this high throughput screening revealed a loop at the end of the CYP3A5 protein which acts as a physical barrier.
"There is a narrower binding pocket for CYP3A5, which prevents CYP3A4 inhibitors from binding," Chen added.
Using this data, the team optimized inhibitor structure to maximize selectivity and potency, ultimately achieving a 46-fold difference when comparing CYP3A4 inhibition to CYP3A5 inhibition.
"Our goal is to improve the potency but maintain the selectivity of our CYP3A4-selective inhibitors," Chen concluded. "These compounds are the starting points for achieving that, which is now feasible because of the structural basis of selectivity we have uncovered."