Design of Novel Synthetic Peptides Including Cyclic Conformationally and Topgraphically Constrained Analogs.

The properties of a peptide in biological systems are dependent on its structure. Thus, our ability to use rational design for the generation of useful peptides is dependent on our commensurate ability to determine the specific relationships of molecular structure to biological activity. The ability to recognize these relationships is complicated by a variety of uncertainties, both in the assay systems and in the interpretation of data. One major complicating factor is the difficulty in ascertaining the three-dimensional structure of the peptide itself. Most peptides are inherently flexible and, thus, assume many conformations in solution. It is difficult to determine which of these conformations is responsible for the observed activity of the peptide, and many peptides may be active in more than one conformation. The use of conformational constraints has been helpful in elucidating these structure-function relationships. The logic is that if the peptide is restricted to a particular conformation or closely related family of conformations, then the activity measured will reflect that structure. Although a perfectly rigid molecule is impossible, by creating analogs with prescribed structural motifs, one can begin to ascribe certain biological activities to their causal structures. In favorable cases, knowledge of requirements for peptide activity at receptor- and enzyme-active sites can be obtained. [ABSTRACT FROM AUTHOR]