β-Sheet breakers based on trimeric aminopyrazoles:

A totally different way for noncovalent interference with protein aggregation focusses on molecular recognition of its peptidic backbone. Only in a β-sheet all NH and C=O groups of the peptide main chain point up or down, respectively, and may be bound by complementary receptor molecules with the appropriate DAD pattern of hydrogen bonds. Several years ago, we have introduced a new binding motif for the efficient capping for growing b-sheets, and could demonstrate that already the lead structure of trimeric 3-aminopyrazole-5-carboylic acids are able to dissolve existing Ab fibrils and convert them into nontoxic aggregates.

Covalent linkage to dodecapeptides selected by phage-display (D. Willbold) furnished new hybrid compounds with β-sheet selector and β-sheet breaker abilities, which displayed new characteristics in a synergistic way: thus in cell culture formation of extremely toxic oligomers was completely suppressed and collapsed nerve potentials were restored.

Very recently, we also created hybrid compounds from trimeric aminopyrazoles and scFv-antibodies, with a high specificity towards the unfolded N-Terminus (Aβ1-8) or with camelide antibodies (C. Korth, Neurologie Düsseldorf), which prefer Aβ oligomers. All these new hybrid compounds serve the same one purpose: to better understand misfolding of Alzheimer’s and related peptides and to discover new opportunities for external interference, which may be further developed into prediagnostic and therapeutic agents.

References

• Interactions of Small Protected Peptides with Aminopyrazole Derivatives: The Efficiency of capping a b-Sheet Model in the Gas Phase. H. Fricke, A. Gerlach, C. Unterberg, M. Wehner, T. Schrader, M. Gerhards, Angew. Chem. Int. Ed. 2009, 48, 900-904.

• Gesteigerte Wirksamkeit durch Synergismus: Verknüpfung unabhängiger Wirkstoffklassen zu Hybridsubstanzen. A. Müller-Schiffmann, J. März, A. Andrjevna, R. Rönicke, D. Bartnik, O. Brener, J. Muyrers, A. Horn, K. Gottmann, K. Reymann, S. A. Funke, L. Nagel-Steger, C. Moriscot, G. Schoehn, H. Sticht, D. Willbold, T. Schrader, C. Korth. Angew. Chem. Int. Ed. 2010, 122, 8925–8928.

• Rational Design of ß-Sheet Ligands against Aß42-induced toxicity. K. Hochdörffer, J. März-Berberich, L. Nagel-Steger, M. Epple, W. Meyer-Zaika, A.H.C. Horn, H. Sticht, S. Sinha, G. Bitan, T. Schrader, J. Am. Chem. Soc.2011, 133, 4348-4358.