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Updated: Dec 21, 2025
10:29
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
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Nucleoside Reverse Transcriptase Inhibitor Interaction with Human Equilibrative Nucleoside Transporters 1 and 2
Siennah R Miller1, Raymond K Hau1, Joseph L Jilek1
1College of Pharmacy, Department of Pharmacology and Toxicology (S.R.M., R.K.H., J.L.J., N.J.C.) and College of Medicine, Department of Physiology (M.N.M., S.H.W.), University of Arizona, Tucson, Arizona.
Summary
This study demonstrates that HeLa cells effectively model equilibrative nucleoside transporters (ENTs) at the blood-testis barrier. It reveals how nucleoside reverse-transcriptase inhibitors interact with ENT1 and ENT2, aiding drug development for male reproductive health.
Area of Science:
- Pharmacology
- Cell Biology
- Biochemistry
Background:
- Equilibrative nucleoside transporters (ENTs) are crucial for nucleoside transport across the blood-testis barrier (BTB).
- Understanding NRTI interactions with ENTs is vital for male reproductive tract drug disposition.
- HeLa S3 cells express ENT1 and ENT2, serving as a model for BTB transporters.
Purpose of the Study:
- To compare the interaction of selected nucleoside reverse-transcriptase inhibitors (NRTIs) with ENT1 and ENT2 in HeLa S3 cells.
- To establish a reliable in vitro model for studying ENT function relevant to the BTB.
- To determine the substrate and inhibitor profiles of NRTIs for ENT1 and ENT2.
Main Methods:
- Utilized NBMPR to differentiate ENT1 and ENT2-mediated [3H]uridine uptake.
- Performed kinetic analysis of [3H]uridine uptake for ENT1 and ENT2.
- Assessed NRTI effects on ENT transport using liquid chromatography-tandem mass spectrometry and radiolabeled compounds.
Main Results:
- NBMPR exhibited differential inhibition of ENT1 (IC50 = 11.3 nM) and ENT2 (IC50 = 9.6 μM).
- Kinetic analysis revealed distinct K_t values for ENT1 (13.6 μM) and ENT2 (108.9 μM) but similar J_max.
- Entecavir was identified as an ENT substrate, abacavir as an ENT inhibitor, and zidovudine uptake as carrier-mediated but not an ENT substrate.
Conclusions:
- HeLa S3 cells provide a valid model for studying ENT selectivity relevant to the BTB.
- The study differentiates NRTI interactions with ENT1 and ENT2, clarifying their transport mechanisms.
- Findings support targeted drug development for compounds that can navigate the blood-testis barrier effectively.
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