Conformational constraints, peptide

Y. Tian, et al., (2002). Structure-affinity relationships in the gp41 ELDKWA epitope for the HIV-(l) neutralizing monoclonal antibody F-2(5) effects of side-chain and backbone modifications and conformational constraints. /. Peptide Res. 59, 264—276. 

Figure 8 A joint principal coordinate projection of the occupied regions in the conformational spaces of linear (Ala) (triangles) and its conformational constraint counterpart, cyclic-CAla) (squares), onto the optimal 3D principal axes. The symbols indicate the projected conformations, and the ellipsoids engulf the volume occupied by the projected points. This projection shows that the conformational volume accessible to the cyclic analog is only a small subset of the conformational volume accessible to the linear peptide, (Adapted from Ref. 41.)...

The strategy of introducing non-natural aminoacids into the oxytocin peptide skeleton in order to make antagonists has also been exploited by Havaas et al. [51], who replaced the proline at the 7-position with sarcosine and modified the tyrosine residue at the 2-position to introduce further conformational constraint. A representative example is shown, (13), with a... 

A.F. Spatola, Peptide backbone modifications A structure-activity analysis of peptides containing amide bond surrogates, conformational constraints, and related backbone replacements, in B. Weinstein(Ed.), Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, Marcel Dekker, New York, 1983, pp. 267-357. 

It is more difficult to prepare a chiral a,a-dialkylammo acid. Nevertheless, when such analogues are incorporated into the backbone of a peptide chain, analogues with modified properties are obtained. In this context, such residues have been evaluated as a new type of conformational constraint for the synthesis of enzyme-resistant agonists and antagonists of bioactive peptides. Here, the asymmetric synthesis or the resolution of the chiral quaternary amino acid is necessary and numerous procedures, which have recently been reviewed, were developed to produce the requisite amino acids in enantiomerically pure form. 

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... 

Novel properties of peptides can be obtained by incorporation of Saa. Peptides are characteristically highly flexible molecules whose 3D structure is strongly influenced by their environment. Their often unordered conformation in solution complicates their use in determining the receptor bound bioactive structure.182,831 Conformational constraints,184-881 cyclization/891 and/or replacement of the peptide backbone or parts of it162 90-921 can provide information on the required conformation for biological activity. 

As mentioned above, these three subunits were designed to form a first a-helical turn in which the four amide groups are ideally oriented to participate in the H-bond network of an a-helix. Peptides that are linked to these templates adopt an a-helical conformation due to the conformational constraint induced by the high inherent a-helix propensity of the template and the H-bond network that is initiated by the proper orientation of the carbonyl groups. Thus, helix induction is achieved by the combination of steric and electronic properties of the three subunits. 

A large number of amino acid and dipeptide derivatives with built-in conformational constraints have been synthesized and incorporated into biologically active peptides (reviewed in Hruby, 1982). In this review we shall consider only those modifications that appear to be generally applicable and for which the amino acids are either commercially available or can be prepared relatively easily. 

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