Authors: Urry, Dan W.; Urry, Kelley D.; Szaflarski, Witold; Nowicki, Michal; Zabel, Maciej

Source: Current Pharmaceutical Design, Volume 15, Number 24, August 2009 , pp. 2833-2867(35)

Publisher: Bentham Science Publishers

Abstract:

The mechanism is presented whereby simultaneous hydrolysis of two molecules of ATP in the ATP-binding cassette (ABC) exporter protein, Sav 1866, opens a transmembrane channel to pump drug out of the cell and confers drug resistance, e.g., gives rise to methicillin resistant Staphylococcus aureus, MRSA.

The proposed mechanism suggests pharmaceutical design strategies for overloading the capacity of two molecules of ATP to open access to the channel for export. Structural homology of Staphylococcus aureus, Sav 1866, to human P-glycoprotein and MRP2, suggests a similar mechanism could be relevant to human carcinoma cells.

The transport mechanism utilizes two thermodynamic quantities - ΔGHA, the change in Gibbs free energy for hydrophobic association, and ΔGap, an apolar-polar repulsive free energy for hydration, derived from studies on designed elasticcontractile model proteins (ECMPs). These quantities also allow design of remarkably biocompatible ECMPs as drug delivery vehicles with remarkable control of release profiles and of ECMPs that provide the means of developing pharmaceuticals for blocking multi-drug resistance.

Document Type: Research article

Affiliations: 1: Bioelastics Inc., 2423 Vestavia Drive, Vestavia Hills, AL 35216-1333, USA.

Publication date: 2009-08-01

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• Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.
  
  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

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