title: Design, synthesis, and biological evaluation of (S)-valine thiazole-derived cyclic and noncyclic peptidomimetic oligomers as modulators of human P-glycoprotein (ABCB1).
abstract: Multidrug resistance caused by ATP binding cassette transporter P-glycoprotein (P-gp) through extrusion of anticancer drugs from the cells is a major cause of failure in cancer chemotherapy. Previously, selenazole-containing cyclic peptides were reported as P-gp inhibitors and were also used for co-crystallization with mouse P-gp, which has 87 % homology to human P-gp. It has been reported that human P-gp can simultaneously accommodate two to three moderately sized molecules at the drug binding pocket. Our in silico analysis, based on the homology model of human P-gp, spurred our efforts to investigate the optimal size of (S)-valine-derived thiazole units that can be accommodated at the drug binding pocket. Towards this goal, we synthesized varying lengths of linear and cyclic derivatives of (S)-valine-derived thiazole units to investigate the optimal size, lipophilicity, and structural form (linear or cyclic) of valine-derived thiazole peptides that can be accommodated in the P-gp binding pocket and affects its activity, previously an unexplored concept. Among these oligomers, lipophilic linear (13) and cyclic trimer (17) derivatives of QZ59S-SSS were found to be the most and equally potent inhibitors of human P-gp (IC50 =1.5 μM). As the cyclic trimer and linear trimer compounds are equipotent, future studies should focus on noncyclic counterparts of cyclic peptides maintaining linear trimer length. A binding model of the linear trimer 13 within the drug binding site on the homology model of human P-gp represents an opportunity for future optimization, specifically replacing valine and thiazole groups in the noncyclic form.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439 (USA).
authors.forename: Satyakam
authors.initials: S
authors.lastname: Singh
authors.forename: Nagarajan Rajendra
authors.initials: NR
authors.lastname: Prasad
authors.forename: Khyati
authors.initials: K
authors.lastname: Kapoor
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Chufan
authors.forename: Bhargav A
authors.initials: BA
authors.lastname: Patel
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D001896:Boron Compounds / Q000737:chemistry; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D057786:Peptidomimetics; D038761:Photobleaching / Q000187:drug effects; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001896:Boron Compounds; D009842:Oligopeptides; D010456:Peptides, Cyclic; D057786:Peptidomimetics; D013844:Thiazoles; C539646:cyclic-tris-(R)-valineselenazole; C057231:valine thiazole; D014633:Valine
keywords: ABC transporters; P-glycoprotein; molecular modeling; multidrug resistance; peptide mimics