title: Rapid isolation of peptidic inhibitors of the solute carrier family transporters OATP1B1 and OATP1B3 by cell-based phage display selections.
abstract: OATP1B1 and OATP1B3 (1B3) are members of organic anion-transporting polypeptides (OATPs), a family of sodium-independent organic anion membrane transporters that contribute to transport of various drugs. To identify peptide inhibitors of OATP1B1, we developed a direct selection system on live cells using phage-displayed peptide libraries. Selections against OATP1B1 overexpressed cell-lines yielded three unique peptides able to inhibit the transport function of OATP1B1 and 1B3. Affinity maturation of one peptide led to identification of two peptides that demonstrated improved inhibition efficacy on drug uptake mediated by OATP1B1 and 1B3. We anticipate that these peptides will assist the identification of novel substrates for OATP1B1 and 1B3. Moreover, our selection system is a practical method for generating inhibitors of other membrane transporters.
authors.affiliation: Banting and Best Department of Medical Research and Department of Molecular Genetics, The Donnelly Centre, University of Toronto, Toronto, ON Canada.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Arita
authors.affiliation: Absorption Systems LP, Exton, PA, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Allen
authors.affiliation: Banting and Best Department of Medical Research and Department of Molecular Genetics, The Donnelly Centre, University of Toronto, Toronto, ON Canada.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Absorption Systems LP, Exton, PA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Absorption Systems LP, Exton, PA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Absorption Systems LP, Exton, PA, USA.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Owen
authors.affiliation: Absorption Systems LP, Exton, PA, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Dentinger
authors.affiliation: Banting and Best Department of Medical Research and Department of Molecular Genetics, The Donnelly Centre, University of Toronto, Toronto, ON Canada. Electronic address: sachdev.sidhu@utoronto.ca.
authors.forename: Sachdev S
authors.initials: SS
authors.lastname: Sidhu
mesh_terms: D000595:Amino Acid Sequence; D001692:Biological Transport / Q000187:drug effects; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008969:Molecular Sequence Data; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D019151:Peptide Library; D010455:Peptides; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
keywords: OATP1B1; OATP1B3; Organic anion-transporting polypeptides; Peptide inhibitor; Phage-display