Alpha-helices play a critical role in the structure and function of proteins. Usually the alpha-helices involved in biomolecular recognitions consist of 8-15 amino acid residues. These small domains, however, do not remain structured when excised from proteins. This thesis reports a new approach to stabilize short peptides into alpha-helical conformations: the backbone hydrogen-bond between the carbonyl group of the i^th residue and amide proton of the i+4^th residue in an alpha-helix is replaced by a carbon-carbon bond. An important feature of this HBS approach is that it retains all amino acid side chain functionality for molecular recognition.

Chapter 2 describes the potential of this method for the synthesis of two 10-residue alpha-helices representing two different biologically relevant domains. We extensively characterized these two sets of artificial helices by NMR and circular dichroism spectroscopies and found that the hydrogen-bond surrogate approach can afford well-defined short alpha-helical structures from sequences that do not spontaneously form alpha-helical conformations.

Chapter 3 describes the effect of the core nucleation template on the overall helicities of the HBS-helices and demonstrates that the macrocycle which most closely mimics the 13-membered hydrogen-bonded alpha-turn in alpha-helices also affords the most stable artificial alpha-helix. We also investigate the stability of these synthetic helices through classical helix-coil parameters and find that the denaturation behavior of HBS alpha-helices agrees with the theoretical properties of a peptide with a well-defined and stable helix nucleus.

Chapter 4 examines the bioactivities of these artificial helices by targeting anti-apoptotic protein Bcl-xL. HBS helices derived from pro-apoptotic BAK, BAX and BID protein BH3 domains were shown to bind Bcl-xL protein, an anti-apoptotic protein, with high affinities. Preliminary results to test the proteolytic stability of HBS helices also show that HBS helices were more stable than the unconstrained peptides.

Chapter 5 discusses the potency of HBS alpha-helices to inhibit HIV fusion in cell culture. Several HBS peptides were prepared to test their in vitro affinities for a stable trimeric coiled coil. The successful HBS peptide bound the target with low micromolar affinities. One of the HBS helices inhibited the HIV-1 fusion with an IC₅₀ of 42.7 μM.