engleski

Hydrazino peptidomimetics as modulators of protein-protein interactions

Design and synthesis of peptidomimetics represent an important field in chemistry, pharmacology and material science, as they circumvent the numerous limitations of natural peptides. Self-structural organizations important for biological functions of peptide and proteins, such as turns, helices, sheets and loops, can be accessed by chemical modifications of amino acids or peptides. Replacement of C atom in -amino acids with nitrogen leads to hydrazino peptides, a class of peptidomimetics able to adopt various secondary structures. Although hydrazino-based peptidomimetics showed promising biological activities, their wider exploitation is hampered by challenging synthesis. We aimed to develop solid-phase methodology for smooth incorporation of hydrazido derivatives of natural a-amino acids into peptide chain and study interaction of designed peptidomimetics with biomolecules. Modulation of protein–protein interactions (PPIs) have emerged as one of the main challenges in chemical biology and drug discovery. Therefore, as a biological target, we chose a well-described p53-hDM2 model. Disruption of the p53-hDM2 interaction is an important goal for cancer therapy. To explore the utility of hydrazino-based peptidomimetics to interfere with these interaction, we designed a small library of compounds based on the biologically active octapeptide fragment of p53 protein (Figure 1). Three amino acids, Phe, Trp and Leu, directly participate in interaction, so we decided to replace two of them (Phe and Leu) and Tyr adjacent to Trp, with their hydrazino analogues. Hydrazino derivatives were prepared by nucleophilic substitution of D-amino acid-derived α-bromo acids with hydrazine hydrate and subsequent Fmoc-group introduction to N position. Solid-phase methodology was optimized for hydrazino building bloks, and peptidomimetics isolated in good yealds. Compounds were studied by spectroscopic methods, their affinities determined by isothermal titration calorimetry and compared with the native p53 sequence that binds hDM2.

peptidomimetics; hydrazino acids; protein-protein interaction

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