Speaker
Description
Abstract:
Background: Human pregnancy relies on tightly controlled maternal estradiol (E2) levels, which are essential to maintain the pregnancy to full term. However, recent studies have indicated hormonal dysregulation of pregnant people receiving antiretroviral therapy, including the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. Effectively, efavirenz was associated with a significant decrease in E2 levels which further correlated with infants of small for gestational age and low birth weights [McDonald et al.: Clin. Infect. Dis. 66 (2018) 428].
Methods: To test if antiviral drugs inhibit aromatization of androstenedione (A4) to estrone (E1) by CYP19A1, the rate limiting step in placental E2 synthesis, we developed an in vitro CYP19A1 inhibition assay based on LC-MS quantification of E1 to screen HIV antiretroviral drugs and then determined the inhibition dose response (IC50) for the most potent compounds. Furthermore, molecular docking analysis was employed to determine the specific molecular interactions between the NNRTIs and the CYP19A1 active site residues.
Results: Among the HIV drugs tested, four displayed over 50% inhibition of recombinant CYP19A1 at 20 µM, with efavirenz and etravirine fully inhibiting aromatization of A4. The inhibition potency (IC50) for the NNRTI drugs was 0.817 µM for efavirenz and 0.0542 µM for etravirine.
Conclusions: Our findings unveil a novel molecular pathway for drug-hormone interaction (DHI) toxicity in pregnant people receiving NNRTIs. Furthermore, the nanomolar inhibition observed with these drugs may provide new scaffold for the next generation of non-steroidal aromatase inhibitors.
Acknowledgments:
Supported by the NIH NIAID grant # R01 AI183687.
