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Selective interactions of HIV protease inhibitors with human plasma membrane monoamine transporter and organic cation transporters (1064.13)
Author(s) -
Duan Haichuan,
Pan Yongmei,
Swaan Peter,
Unadkat Jashvant,
Wang Joanne
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1064.13
Subject(s) - organic cation transport proteins , ritonavir , transporter , pharmacophore , chemistry , monoamine neurotransmitter , saquinavir , pharmacology , norepinephrine transporter , biochemistry , human immunodeficiency virus (hiv) , biology , virology , antiretroviral therapy , viral load , gene , receptor , serotonin
The plasma membrane monoamine transporter (PMAT, SLC29A4) is a novel polyspecific organic cation transporter that shares significant substrate and inhibitor overlaps with organic cation transporters (OCTs) in the SLC22 family. Currently, there are no PMAT‐selective inhibitors available to distinguish PMAT activities from those of OCTs. In this study, we first identified HIV protease inhibitors (HIV PIs) as potential PMAT inhibitors through computer‐aided virtual screening using previously developed pharmacophore models. We then developed nonradioactive fluorescent substrate‐based uptake assays for PMAT and OCT1‐3. These assays demonstrated excellent accuracy and robustness for inhibitor screening and characterization. Using these assays, we characterized the interaction of human PMAT and OCT1‐3 with a panel of HIV PIs. Our results showed that PMAT was broadly and strongly inhibited by most HIV PIs whereas OCT2 and OCT3 were relatively resistant to PIs. OCT1 selectively interacted with PIs and was most strongly inhibited by ritonavir and saquinavir. Uptake experiments with [3H]ritonavir further suggested that it is likely a transportable substrate for PMAT. Our results revealed that PMAT and OCTs possess differential sensitivity towards HIV PIs which could have important implications for understanding clinical drug interactions with HIV PIs. Grant Funding Source : Supported by NIH Grants GM066233 and GM066233‐07S1.