Development of polyvalent inhibitors of P-glycoprotein and metal-triggered self-assembly of collagen peptides
A majority of patients become resistant to a broad spectrum of anti-cancer therapeutics over time. One of the most important mechanisms of resistance is the over-expression of P-glycoprotein (P-gp). P-gp acts as a "hydrophobic vacuum cleaner," extruding drugs from the plasma membrane before they reach the cytosol. In our initial studies, we designed and synthesized a small library of bivalent agents that were composed of two copies of the P-gp substrate emetine, linked by tethers of varied composition and lengths. These agents became potent inhibitors of P-gp. More importantly, these compounds were able to reverse the multidrug resistance phenotype in resistance cell lines. We have implemented this strategy to another well-known P-gp substrate, quinine. This new class of inhibitors was used as a platform for the design of our second generation inhibitors of P-gp. These next generation, reversibly-linked, drug homodimers have two functions. First, they should effectively inhibit P-gp by directly interacting with its binding sites. Second, they should disassemble in the reducing intracellular environment of the cell to re-generate the original monomeric drugs. Several quinine-based homodimeric inhibitors were synthesized and many were found to be potent inhibitors of P-gp. Additionally, we developed a ligand-modified, collagen triple helical peptide that rapidly and reversibly assembles in the presence of metal ions to form microspheres of reproducible size and shape. Folding intermediates are observed at low temperature and short incubation times that are composed of curved layered sheets. We showed that the surface and the core of the microspheres readily sequester small organic fluorophores and the chemotherapeutic agent doxorubicin. We also demonstrated that unsatisfied metal/ligands exist on the surface and within the micropheres, and that these may be easily modified with His-tag functionalized molecules. These unprecedented microscopic structures offer opportunities in many areas, including drug delivery, tissue engineering, and regenerative medicine.
Chmielewski, Purdue University.
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