Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

ABSTRACT Miltefosine (hexadecylphosphocholine) is the first orally active drug approved for the treatment of leishmaniasis. We have previously shown the involvement of LtrMDR1, a P-glycoprotein-like transporter belonging to the ATP-binding cassette superfamily, in miltefosine resistance in Leishmania. Here we show that overexpression of LtrMDR1 increases miltefosine efflux, leading to a decrease in drug accumulation in the parasites. Although LtrMDR1 modulation might be an efficient way to overcome this resistance, a main drawback associated with the use of P-glycoprotein inhibitors is related to their intrinsic toxicity. In order to diminish possible side effects, we have combined suboptimal doses of modulators targeting both the cytosolic and transmembrane domains of LtrMDR1. Preliminary structure-activity relationships have allowed us to design a new and potent flavonoid derivative with high affinity for the cytosolic nucleotide-binding domains. As modulators directed to the transmembrane domains, we have selected one of the most potent dihydro-β-agarofuran sesquiterpenes described, and we have also studied the effects of two of the most promising, latest-developed modulators of human P-glycoprotein, zosuquidar (LY335979) and elacridar (GF120918). The results show that this combinatorial strategy efficiently overcomes P-glycoprotein-mediated parasite miltefosine resistance by increasing intracellular miltefosine accumulation without any side effect in the parental, sensitive, Leishmania line and in different mammalian cell lines.

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Jatrophane Diterpenes as P-Glycoprotein Inhibitors. First Insights of Structure−Activity Relationships and Discovery of a New, Powerful Lead

Journal of Medicinal Chemistry ◽

10.1021/jm030787e ◽

2003 ◽

Vol 46 (15) ◽

pp. 3395-3402 ◽

Cited By ~ 55

Author(s):

Gabriella Corea ◽

Ernesto Fattorusso ◽

Virginia Lanzotti ◽

Orazio Taglialatela-Scafati ◽

Giovanni Appendino ◽

...

Keyword(s):

Structure Activity Relationships ◽

Structure Activity ◽

P Glycoprotein ◽

Glycoprotein Inhibitors

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Hydrophobic moments as physicochemical descriptors in structure-activity relationship studies of P-glycoprotein inhibitors

Monatshefte für Chemie - Chemical Monthly ◽

10.1007/s00706-007-0819-7 ◽

2008 ◽

Vol 139 (4) ◽

pp. 401-405 ◽

Cited By ~ 6

Author(s):

Gerhard König ◽

Peter Chiba ◽

Gerhard F. Ecker

Keyword(s):

Structure Activity Relationship ◽

Activity Relationship ◽

Structure Activity ◽

P Glycoprotein ◽

Physicochemical Descriptors ◽

Glycoprotein Inhibitors

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Intestinal P-glycoprotein: pharmacokinetic implications and approaches for enhancement of oral bioavailability of its substrates

Journal of Pharmaceutics and Therapeutics ◽

10.18314/jpt.v1i1.34 ◽

2016 ◽

Vol 1 (1) ◽

Author(s):

Manish Nivsarkar ◽

Ranjeet Prasad Dash

Keyword(s):

Chemical Nature ◽

The Body ◽

Drug Efflux ◽

Therapeutic Drugs ◽

P Glycoprotein ◽

Drug Efflux Pumps ◽

Glycoprotein Inhibitors ◽

Carrier Systems ◽

Glycoprotein Inhibition ◽

Exogenous Substances

A variety of drug transporters expressed in the body control the fate of drugs by affecting absorption, distribution, and elimination processes. In intestine, the transporters mediate the influx and efflux of endogenous or exogenous substances depending on their affinity to intestinal carrier systems as well as their chemical nature. Of prime interest are drug efflux pumps like P-glycoprotein that are recognized to pose functional role in determining the pharmacokinetics of drugs administered by peroral as well as parenteral route. Various formulation approaches are opted in order to overcome this P-glycoprotein mediated drug efflux. Moreover, broad substrate recognition by this protein and clinical implications of its inhibition lead to design and development of novel P-glycoprotein inhibitors that includes some therapeutic drugs and daily foods and beverages. Inhibition of P-glycoprotein improves intestinal absorption and tissue distribution while reducing the substrate metabolism and its elimination. Some of the pharmaceutical excipients have also shown P-glycoprotein inhibition activity. In this review, we will be discussing about the various approaches that can be explored to reduce P-glycoprotein mediated drug efflux and improve the bioavailability of its substrates.

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Application of Three-Dimensional Quantitative Structure-Activity Relationships of P-Glycoprotein Inhibitors and Substrates

Molecular Pharmacology ◽

10.1124/mol.61.5.974 ◽

2002 ◽

Vol 61 (5) ◽

pp. 974-981 ◽

Cited By ~ 141

Author(s):

Sean Ekins ◽

Richard B. Kim ◽

Brenda F. Leake ◽

Anne H. Dantzig ◽

Erin G. Schuetz ◽

...

Keyword(s):

Three Dimensional ◽

Quantitative Structure ◽

Structure Activity Relationships ◽

Structure Activity ◽

P Glycoprotein ◽

Quantitative Structure Activity Relationships ◽

Glycoprotein Inhibitors

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Chimeras of the ABC drug transporter Cdr1p reveal functional indispensability of transmembrane domains and nucleotide-binding domains, but transmembrane segment 12 is replaceable with the corresponding homologous region of the non-drug transporter Cdr3p

Microbiology ◽

10.1099/mic.0.28471-0 ◽

2006 ◽

Vol 152 (5) ◽

pp. 1559-1573 ◽

Cited By ~ 17

Author(s):

Preeti Saini ◽

Naseem Akhtar Gaur ◽

Rajendra Prasad

Keyword(s):

Cell Surface ◽

Drug Transport ◽

Nucleotide Binding ◽

Transmembrane Domains ◽

Homologous Region ◽

Drug Efflux ◽

Drug Transporter ◽

Transmembrane Segment ◽

Recombinant Strains ◽

Binding Domains

The molecular basis of the broad substrate recognition and the transport of substrates by Cdr1p, a major drug efflux protein of Candida albicans, is not well understood. To investigate the role of transmembrane domains and nucleotide-binding domains (NBDs) of Cdr1p in drug transport, two sets of protein chimeras were constructed: one set between homologous regions of Cdr1p and the non-drug transporter Cdr3p, and another set consisting of Cdr1p variants comprising either two N- or two C-terminal NBDs of Cdr1p. The replacement of either the N- or the C-terminal half of Cdr1p by the homologous segments of Cdr3p resulted in non-functional recombinant strains expressing chimeric proteins. The results suggest that the chimeric protein could not reach the plasma membrane, probably because of misfolding and subsequent cellular trafficking problems, or the rapid degradation of the chimeras. As an exception, the replacement of transmembrane segment 12 (TMS12) of Cdr1p by the corresponding region of Cdr3p resulted in a functional chimera which displayed unaltered affinity for all the tested substrates. The variant protein comprising either two N-terminal or two C-terminal NBDs of Cdr1p also resulted in non-functional recombinant strains. However, the N-terminal NBD variant, which also showed poor cell surface localization, could be rescued to cell surface, if cells were grown in the presence of drug substrates. The rescued chimera remained non-functional, as was evident from impaired ATPase and efflux activities. Taken together, the results suggest that the two NBDs of Cdr1p are asymmetric and non-exchangeable and that the drug efflux by Cdr1p involves complex interactions between the two halves of the protein.

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