Potent and Fully Noncompetitive Peptidomimetic Inhibitor of Multidrug Resistance P-Glycoprotein

Abstract

N(α)-Boc-l-Asp(OBn)-l-Lys(Z)-OtBu (reversin 121, 1), an inhibitor of the P-gp ABC transporter, was used to conceive compounds inhibiting the drug efflux occurring through the Hoechst 33342 and daunorubicin transport sites of P-gp, respectively H and R sites. Replacement of the aspartyl residue by trans-4-hydroxy-l-proline (4(R)Hyp) gave compounds 11 and 15 characterized by half-maximal inhibitory concentrations (IC(50)) of 0.6 and 0.2 μM, which are 2- and 7-fold lower than that of the parent molecule. The difference in IC(50) between 11 and 15 rests on the carbonyl group of the peptidyl bond, reduced in 15. Those compounds are rather specific of P-gp, having no or limited activity on MRP1 and BCRP. 15 displayed no marked cytotoxicity up to 10-fold its IC(50). Importantly, 15 equally inhibited the Hoechst 33342 and daunorubicin effluxes through a typical noncompetitive inhibition mechanism, suggesting its binding to a site different from the H and R drug-transport sites.

Herb–Drug Interactions: Challenges and Opportunities for Improved Predictions

“…Compared with metabolismbased interactions, mechanistic information about transporter-based interactions is limited, although the knowledge gap is beginning to narrow (Han, 2011). Similar to drug metabolizing enzymes, transport proteins are susceptible to competitive and noncompetitive reversible inhibition due to the perpetrator blocking the victim drug binding site or causing a conformational change that decreases transport activity, respectively (Arnaud et al, 2010;Harper and Wright, 2013). In addition to these traditional modes of inhibition, the in vitro activity of drug transporters can be modulated by the composition of the cell membrane; however, the clinical consequence remains unclear (Annaba et al, 2008;Molina et al, 2008;Kis et al, 2009;Clay and Sharom, 2013).…”

Overview of P-glycoprotein inhibitors: a rational outlook

“…The only difference between these molecules lies in the presence of a reduced carbonyl group of the peptidyl bond in reversin 15. These compounds were reported as specifically P-gp targeting non-transported inhibitors by binding to an allosteric modulatory site other than H and R sites on the protein (Arnaud et al, 2010).…”

Substrate Binding Stabilizes a Pre-translocation Intermediate in the ATP-binding Cassette Transport Protein MsbA

“…Mouse ABCB1a was recently crystallized with cyclic peptide inhibitors (21). Although the peptide-bound ABCB1a structures identify a substrate-binding surface (1,21,22), these structures appear identical to the drug/nucleotide-free inward-facing ABCB1a and MsbA conformations. The suggestion that the protein structure is unaltered when progressing from a substrate/nucleotide-free apo-state to a substrate-bound state is inconsistent with previously published biochemical data, nearly all of which point to a measurable conformational change (19,(23)(24)(25)(26)(27).…”