Biochemical and pharmacological properties of an allosteric modulator site of the human P-glycoprotein (ABCB1)

Maki, Nazli; Dey, Saikat

doi:10.1016/j.bcp.2006.04.008

Cited by 13 publications

(14 citation statements)

References 36 publications

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“…A strain in which the PDR5 gene is retained, with homologous constitutive high expression, has been used to screen a large (1.89 × 10 6 ) combinatorial d-octapeptide library for efflux pump inhibitors [52]. Another such strain, AD1-8uand its derivatives, have been used extensively to overexpress heterologous fungal efflux pumps for functional analysis and inhibitor screening [35,[53][54][55][56][57][58][59]. Inserting the efflux pump gene of interest after the genomic PDR5 promoter leads to constitutive high levels of efflux pump expression.…”

Section: Heterologous Expression Of Efflux Pumpsmentioning

confidence: 99%

“…This system has been used to express several ABC and MFS efflux pumps, including the human ABC transporter P-gp (HsABCB1) [56] and therefore can also be employed in secondary screens to assess inhibitor specificity. Secondary screening is important because several fungal pump inhibitors ( Figure 2) have also been reported as inhibiting P-gp, including curcumin [90] phenothiazine derivatives [57] propafenone [91] c halcones [92] beauvericin [93] and FK506 (tacrolimus) [94].…”

Section: Albicans Efflux Pump (Camdr1)mentioning

confidence: 99%

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Targeting Efflux Pumps to Overcome Antifungal Drug Resistance

et al. 2016

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Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps.

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Section: Heterologous Expression Of Efflux Pumpsmentioning

confidence: 99%

Section: Albicans Efflux Pump (Camdr1)mentioning

confidence: 99%

Targeting Efflux Pumps to Overcome Antifungal Drug Resistance

et al. 2016

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“…57,58) As most of the ABCB1 substrates are highly hydrophobic and structural analysis implies the presence of substrate recognition sites within the lipid bilayer, cholesterol may easily interact with the sites where drugs are recognized. 59) Alternatively, cholesterol interacts with putative modulator binding site of ABCB1, 60) though these two possibilities are hard to be distinguished.…”

Section: Modulation Of Abcc2/abcc2 Transport Activity By a Variety Ofmentioning

confidence: 99%

ABCC2/Abcc2 Transport Property in Different Species and its Modulation by Heterogeneous Factors

Ito

2008

Drug Metabolism and Pharmacokinetics

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ABCC2/Abcc2 is a member of the ABC transporter family expressed mainly in the liver bile canalicular membrane and involved in the excretion of various kinds of organic anions from hepatocytes into bile. During the drug development process, species differences in the pharmaco- and toxicokinetics of candidate drugs are a major problem. It is possible that ABCC2/Abcc2 transport activity as well as inhibitor sensitivity could lead to a number of phenomena (e.g. a difference in the biliary excretion clearance, a delay in the elimination half-life from the circulating blood and toxic side effects on ABCC2 -mediated drug-drug interactions, such as drug-induced hyperbilirubinemia). From this point of view, it is useful to be able to predict during preclinical development if certain compounds of interest are substrates and/or modulators of ABCC2. Although an in vivo animal model or an in vitro model expressing ABCC2 are useful assay systems, these have some limitations as far as predicting the transport profile of compounds in vivo is concerned. I will present an overview of the species differences in the tissue distribution, function, and also characteristic transport properties of ABCC2/Abcc2 mainly in an in vitro experimental model.

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“…According to the data collected in Table 2, a wide range of therapeutic drugs from adrenergic receptor blockers to immunosuppressive agents interact with both proteins (due to the difficulties mentioned above, no attempt has been made to label P-gp ligands as a substrate or modulator) [6,7,9,11,19,20,24,41,43,47,51,53,58,59,. According to the data collected in Table 2, a wide range of therapeutic drugs from adrenergic receptor blockers to immunosuppressive agents interact with both proteins (due to the difficulties mentioned above, no attempt has been made to label P-gp ligands as a substrate or modulator) [6,7,9,11,19,20,24,41,43,47,51,53,58,59,.…”

Section: Comparative Evaluation Of Ligand Binding Specificity Of Agp mentioning

confidence: 99%

Overlapping Ligand Specificity of P-Glycoprotein and Serum α1-Acid Glycoprotein:Evidences and Potential Implications

Zsila

2007

CDM

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Plasma alpha(1)-acid glycoprotein (AGP) is an important modulator of drug disposition, since it binds and transports of a vast array of pharmaceutical agents. The ABC transporter efflux pump, P-glycoprotein (P-gp), also recognizes and binds a broad range of weakly basic and uncharged xenobiotics. Its efflux activity plays a key role in pharmacokinetics of drugs, and overexpression of P-gp in malignant cells confers multidrug resistance (MDR) to anticancer agents. Comparison of ligand specificities of AGP and P-gp revealed high similarity showing that both proteins interact with the same therapeutic classes of drugs (alpha/beta-blockers, anticancer agents, Ca(2+) antagonists, antipsychotics/neuroleptics, HIV protease inhibitors etc.) as well as with additional endo- and exogenous compounds (steroids, dyes, natural substances). A wealth of examples are presented to show the potential use of drug-AGP binding data to predict drug-P-gp interactions and vice versa. In addition, structural and functional similarities between AGP and P-gp have been highlighted. Based on these data, several proposals have been made: 1) AGP and P-gp might act synergistically in protecting cells from harmful xenobiotics; 2) An extensive shared list of their ligands allows prediction of mutual binding interactions; 3) Interaction of drugs and drug candidates, both with AGP and P-gp, should be considered to optimize pharmacotherapy and to delineate the causes of drug-drug interactions; 4) Structures of known AGP binders could be exploited in searching for novel scaffolds of P-gp modulators to overcome cancer MDR and efflux-mediated resistance in microorganisms and parasites; 5) Novel fluorescent probes for studying P-gp structure and function can be pre-selected among AGP binder agents.

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Biochemical and pharmacological properties of an allosteric modulator site of the human P-glycoprotein (ABCB1)

Cited by 13 publications

References 36 publications

Targeting Efflux Pumps to Overcome Antifungal Drug Resistance

Targeting Efflux Pumps to Overcome Antifungal Drug Resistance

ABCC2/Abcc2 Transport Property in Different Species and its Modulation by Heterogeneous Factors

Overlapping Ligand Specificity of P-Glycoprotein and Serum α1-Acid Glycoprotein:Evidences and Potential Implications

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