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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]

Phosphorylation of tyrosine, serine, and threonine residues by protein kinases has been shown to be a key step in the regulation of many cellular events (1). A better understanding of the molecular basis of this regulatory step is needed in order to gain insight into the specificity of the kinases that control these events. [ABSTRACT FROM AUTHOR]

Phosphorylation and dephosphorylation of proteins represents one of the most widespread and important reactions in the regulation of cellular processes. Specific serine, threonine, or tyrosine residues in substrate proteins become phosphorylated by the action of protein kinases that catalyze the transfer of phosphate from high-energy nucleoside triphosphate. Major proteins in bones, teeth, eggs, and milk are highly phosphorylated. Preparation of phosphopeptides related to sequences of phosphoproteins is important for the study of their properties. Enzymatic methods for the synthesis of phosphopeptides can be useful, but are limited to very specific peptide sequences. [ABSTRACT FROM AUTHOR]

Identification of important or essential residues in proteins and peptides is an overall goal in understanding the mechanism of an enzyme or the binding affinity of a peptide ligand to its receptor. Most early attempts to accomplish this relied on chemical modification of amino acid residues in the native peptide or protein (1). Selectivity of chemical modification reagents has always been the largest problem to overcome when this approach is taken. Isolation of the desired product from the heterogeneous mixture of components and determination of the modified residue or residues become very labor-intensive processes. [ABSTRACT FROM AUTHOR]

Disulfide bridges play a crucial role in the folding and structural stabilization of many important extracellular peptide and protein molecules, including hormones, enzymes, growth factors, toxins, and immunoglo-bulins (1-10). In addition, the artificial introduction of extra disulfide bridges into peptides or proteins allows the creation of conformational constraints that can improve biological activity (11-15) or confer ther-mostability (5, 16-19). Given this intrinsic biological interest, disulfide-con-taining peptides have long been attractive targets for chemical synthesis. Starting with the pioneering work of du Vigneaud on oxytocin (20), the challenge to reproduce and engineer increasingly complex arrays of disulfide bridges as are found in natural peptides and proteins (7, 10, 21- 23) has stimulated the efforts and ingenuities of many peptide chemists. Table 1 provides a representative, but by no means exhaustive, listing of noteworthy syntheses of peptides or small proteins with one or more disulfides. The methods can be readily generalized to analogs in which cysteine residues are replaced by homologs, such as homocysteine, or by sterically restricted derivatives, such as penicillamine (β,β-dimethylcysteine). [ABSTRACT FROM AUTHOR]

Modern peptide synthesis techniques make it straightforward to synthesize linear peptides that are based on amino acid sequences of parent proteins. It is well known that the linear peptide itself often will not share the same activity as the peptide in its original biological environment provided by the native protein. In addition, the scientific reasons for making a peptide will often not be simply to mimic an activity of a protein—whatever it may be—with a small synthetic substitute, but the goal may be to enhance or decrease an activity found in a native protein. Therefore, it is important to be able to modify the conformations and configurations of a linear peptide by cyclizing, polymerizing, or conjugating the peptide. [ABSTRACT FROM AUTHOR]