For de novo design of peptide and protein agonists, most investigators have concentrated their efforts on designing or mimicing the peptide backbone secondary structures ( PHI , PSI space) such as alpha -helix, beta -turn and beta -sheet structures [1-5]. Using this approach, considerable success has been obtained in the de novo design of peptides and proteins with specific secondary structural motifs. In the peptide mimetic area, considerable success has been attained in obtaining non-peptide moieties that can force, mimic or stabilize secondary structures such as alpha -helices or beta -turns [1-3], but most of these structures fail when examined from the viewpoint of the side chain conformational space (topography) since they generally cannot place side chain groups in the same three dimensional space occupied by peptides and proteins. To bridge this gap, and develop a better understaning of hte side chain conformational preferences that determien the biological activities and other properties of peptides that depend on peptide side chain groups for their properties, we and others [6-8] have been developing approaches to the desing and synthesis of novel maino acids and amino acid mimetics that constrain or fix side chain groups in chi space (chi-1(x_1), chi-2(x_2), etc.). We then incorporate these novel amino acids and mimetics into bioactive peptide analogues specifically designed to determien the conformation and topographical three dimensional properties that are critical for biological activity. Examples of such compounds that we have developed and used in biologically active peptides include tetrahydroisoquinoline carboxylic acid (Tic,1) [9], beta -methyltyrosine [10], beta -methyltryptophan [11], and beta -methyl-2'6'-dimethyltyrosine (TMT, 2) [12]. In this paper we report new developments in this area.
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