Alpha-helix Mimetics in Drug Discovery

The a-helix, first characterized by Linus Pauling in 1951 (Pauling et al., 1951), has been extensively studied due to its prevalence in structural biology (Brandon, 1991). a-Helices are the most common secondary conformation in natural proteins ( 40% of amino acids adopt helical conformations) (Ruan et al., 1990). A typical a-helix completes one rotation with 3.6 amino acid residues, each with backbone dihedral angles of 1⁄4 50 and 1⁄4 60 (Fig. 11.1) (Pauling and Corey, 1954). The helix has a rise of 1.5 Å/residue or 5.4 Å/turn (Regan, 1993); as a result, the side chain of a certain residue at position i projects from the same face as those from the i þ 3, i þ 4, and i þ 7 residues in the sequence. There is a large entropy cost in helix formation, which is thermodynamically compensated by the formation of intramolecular hydrogen bonds. The backbone of the a-helix is primarily stabilized by hydrogen bonds between the carbonyl oxygen at the i position and the carboxamide hydrogen at the i þ 4 position (Pauling and Corey, 1954). Because all amides are oriented in the same direction and also the hydrogen bonding sites on the first and last turns are unfulfilled, a macro-dipole is produced (Galoppini and Fox, 1996; Scholtz et al., 1991). The positive end of the dipole is centered at the N-terminus, and the negative end is centered at the C-terminus. The total dipole is augmented if the peptide exists in conditions where both the termini are ionized. a-Helices composed of L-amino acids