Design, Synthesis, and Evaluation of Bicyclic Peptides as Ammonium Ionophores

Nowak, Cheryl L

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Design, Synthesis, and Evaluation of Bicyclic Peptides as Ammonium Ionophores

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A 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 1d-6d may provide better selectivity for ammonium ions over potassium ions than the ammonium ionophore currently used for blood analysis applications, nonactin. Attempts to synthesize 1d, cyclo(L-Glu1â€”D-Val2â€”L-Ala3â€”D-Lys4â€”D-Val5â€”L-Val6)-cyclo-(1Ã£-4Ã¥), were unsuccessful due to poor solubility of the synthetic intermediates. This led to the design of 2d-6d in which specific amino acid residues were chosen to provide higher solubility. Compound 2d, cyclo(L-Glu1â€”D-Ala2â€”D-Ala3â€”L-Lys4â€”D-Ala5â€”L-Ala6)-cyclo-(1Ã£-4Ã¥), was successfully synthesized, but was also too insoluble for characterization or testing in an ion selective electrode (ISE) sensor format. Compound 6d, cyclo(L-Glu1â€”D-Leu2â€”Aib3â€”L-Lys4â€”D-Leu5â€”D-Ala6)-cyclo-(1Ã£-4Ã¥), was successfully synthesized and characterized. When 6d 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 13C-NMR study has been initiated in order to evaluate selectivity of 6d 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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