Design, Synthesis, and Evaluation of Bicyclic Peptides as Ammonium Ionophores
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open in viewerA series of bicyclic peptides have been designed and synthesized to provide ammonium ion complexation sites via hydrogen bonding in a tetrahedral geometry. Molecular modeling dynamics and electrostatics studies indicate that target compounds <B>1d</B>-<B>6d</B> may provide better selectivity for ammonium ions over potassium ions than the ammonium ionophore currently used for blood analysis applications, nonactin. Attempts to synthesize <b>1d</B>, cyclo(L-Glu<SUP>1</SUP>—D-Val<SUP>2</SUP>—L-Ala<SUP>3</SUP>—D-Lys<SUP>4</SUP>—D-Val<SUP>5</SUP>—L-Val<SUP>6</SUP>)-cyclo-(1ã-4å), were unsuccessful due to poor solubility of the synthetic intermediates. This led to the design of <B>2d</B>-<B>6d</B> in which specific amino acid residues were chosen to provide higher solubility. Compound <B>2d</B>, cyclo(L-Glu<SUP>1</SUP>—D-Ala<SUP>2</SUP>—D-Ala<SUP>3</SUP>—L-Lys<SUP>4</SUP>—D-Ala<SUP>5</SUP>—L-Ala<SUP>6</SUP>)-cyclo-(1ã-4å), was successfully synthesized, but was also too insoluble for characterization or testing in an ion selective electrode (ISE) sensor format. Compound <B>6d</B>, cyclo(L-Glu<SUP>1</SUP>—D-Leu<SUP>2</SUP>—Aib<SUP>3</SUP>—L-Lys<SUP>4</SUP>—D-Leu<SUP>5</SUP>—D-Ala<SUP>6</SUP>)-cyclo-(1ã-4å), was successfully synthesized and characterized. When <B>6d</B> was incorporated into an ISE sensor and tested as an ammonium ionophore, results indicated that the bicyclic peptide lacked solubility in the ISE membrane. A <SUP>13</SUP>C-NMR study has been initiated in order to evaluate selectivity of <B>6d</B> for ammonium over potassium and sodium cations in solution. Preliminary results with the potassium ionophore valinomycin as a control have been completed.
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- English
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- etd-0428103-180827
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- 2003
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- 2003-04-28
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