Enhanced Metabolic Stability and Protein-Binding Properties of Artificial α Helices Derived from a Hydrogen-Bond Surrogate: Application to Bcl-xL

Authors


  • We thank Prof. Neville Kallenbach for insightful comments. P.S.A. is grateful for financial support from the NIH (GM073943), the American Chemical Society Petroleum Research Fund, Research Corporation (Cottrell Scholar Award), and the New York State Office of Science, Technology, and Academic Research (James D. Watson investigator). We thank the National Science Foundation for equipment grants for the NMR spectrometer (MRI-0116222) and the capillary LC–ion-trap mass spectrometer (CHE-0234863).

Abstract

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Artificial α helices prepared by the replacement of a hydrogen bond between residues i and i+4 with a carbon–carbon bond can stabilize biologically relevant peptides in helical conformations (1, internal constraint shaded in gray). α Helices based on hydrogen-bond surrogates that mimic Bak BH3 (2, yellow) can bind their expected protein receptor, Bcl-xL (2, green), with high affinity and resist proteolytic degradation.

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