The a-helix accounts for approximately 30 % of protein structures. Often only a few a-helical turns of exposed protein surfaces are recognized by other proteins, DNA, or RNA. [1] Such helical segments in isolation could be valuable biological probes and drug leads, however, the corresponding short peptides ( 15 residues) do not form thermodynamically stable a-helices in water. [2] Helicity can be stabilized to some extent in longer peptides by using helix-nucleating templates, [3] metal-ion clips, [4] unnatural amino acids, [5] or noncovalent [6] and covalent [7][8][9][10] side chain constraints (disulfide, [7] hydrazone, [8] lactam, [9] aliphatic [10] ). Small molecules that stabilize or mimic an a-turn have proven elusive, although a-helix side chains have been mounted on nonpeptidic scaffolds. [11] Here we describe a promising modular strategy for mimicking short a-helices by using consecutive sequences of cyclic pentapeptide modules to form short ahelices that are remarkably stable in water, resistant to protein denaturants, likely tolerant of amino acid substitution, easy to synthesize, and with promising utility for biological applications.
Lactam bridges (i!i + 3, i!i + 4, i!i + 7) have previously been reported to increase a-helicity in longer peptides to some extent. [9] However, consecutive lactam bridges have not previously been reported in short peptides. In principle, cyclic pentapeptides with an i!i + 4 lactam bridge (for example, cyclo(1!5)-[KARAD], 1) are a-turn modules that could be directly linked together through amide bonds. Thus, a dimer would have positions i, i + 4, i + 5, and i + 9 occupied by lactam bridges, while exposed positions i + 1, 2, 3, 6, 7, 8 could in principle be occupied by any peptide side chain (Figure 1). This modular approach to mimicking a-helices is exemplified for the first time below for cyclo(1!5,6!10)-Ac-[KARADKARAD]-NH 2 (2) and cyclo(1!5,6!10,11! 15)-Ac-[KARADKARADKARAD]-NH 2 (3). These compounds are shown to be remarkably stable a-helices in water and maintain their extremely high helicity even under strong denaturing conditions.