Peptides conformationally constrained

G. M. Smith and D. F, Veber, Biochem. Biophys. Res. Commun., 134(2), 907 (1986). Computer-Aided, Systematic Search of Peptide Conformations Constrained by NMR Data. 

Conformationally constrained peptides with Phe, Tyr, Trp, and His units an-nelated with heterocycles 99T585. 

PPII helix-forming propensities have been measured by Kelly et al. (2001) and A. L. Rucker, M. N. Campbell, and T. P. Creamer (unpublished results). In the simulations the peptide backbone was constrained to be in the PPII conformation, defined as (0,VO = ( — 75 25°, +145 25°), using constraint potentials described previously (Yun and Hermans, 1991 Creamer and Rose, 1994). The AMBER/ OPLS potential (Jorgensen and Tirado-Rives, 1988 Jorgensen and Severance, 1990) was employed at a temperature of 298° K, with solvent treated as a dielectric continuum of s = 78. After an initial equilibration period of 1 x 104 cycles, simulations were run for 2 x 106 cycles. Each cycle consisted of a number of attempted rotations about dihedrals equal to the total number of rotatable bonds in the peptide. Conformations were saved for analysis every 100 cycles. Solvent-accessible surface areas were calculated using the method of Richmond (1984) and a probe of 1.40 A radius. 

Diketopiperazines (DKPs) are the smallest naturally occurring cyclic peptides. They are folded head-to-tail and conformationally constrained by a six-membered ring with the side chains orientated in a spatially defined manner. The DKP core... 

Nisin, because of its continued use as a preservative for more than 30 years 661 became an obvious target for a total synthesis 13 To date, it remains the only naturally occurring lanthionine peptide for which this feat has been achieved. In contrast to the lanthionine peptide syntheses of most other approaches already discussed, the total synthesis of nisin is based on a solution-synthesis strategy. Whilst, the total synthesis of the pentacyclic, 34-residue peptide nisin also demonstrated that such syntheses are not a commercially viable option for large amounts of lantibiotics, they have opened the way to useful synthetic methods for the synthesis of novel conformationally constrained peptides and peptidomimetic compounds. 

Conotoxins are small (10-30 amino acids), disulphide-rich, conformationally constrained peptides produced by marine mollusks such as cone snails. The fish-hunting snails, in particular Conus geographus, have been extensively studied. Depending upon the arrangement of disulphide bonds and the number of residues between cysteines, five or more classes of conotoxin can be structurally identified ... 

The asymmetric synthesis of conformationally constrained a-amino acids and their incorporation into peptides are currently topics of great interest [47]. Much sought after are fused bicyclic a-amino acids having the N atom incorporated into a ring system [48]. Many of these amino acids display interesting pharmacological activities, and they have served as building blocks for the synthesis of pep-... 

The ligand-based approach of conformationally constrained peptides has been widely used. The process involves the incorporation of conformational constraints into known peptides, either agonist or antagonist, which enforce a... 

Insertion of two overlapping i, i + 4 lactam bridges in the terminally protected hexa-peptide Boc-Lys-Lys-Ala-Ala-Asp-Asp-OPac results in a highly conformationally constrained structure 27 (Scheme 16).[l52 CD spectra showed a rigid structure that exhibited only partial melting at high temperature, while NMR studies in TFE-d3/H20 revealed a predominantly a-helical structure, as judged by observed NOEs. 

Cyclic peptides are of interest as turn mimetics or as conformationally constrained peptide analogs. The cyclization of peptides can either be performed after cleavage from the support in solution (see, e.g. [58]) or while still on the support. Besides cycli-zations of the peptide backbone, peptides can be cyclized through their side chains or by means of a non-natural spacer. To cyclize the backbone of a peptide on an insoluble support, the peptide must be attached to the support either by a backbone amide linker [59] or via the side chain of an amino acid [60] (Figure 16.7). 

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