Aspartate and glutamate mimetic structures in biologically active compounds.
Glutamate and aspartate are frequently recognized as key structural elements for the biological activity of natural peptides and synthetic compounds. The acidic side-chain functionality of both the amino acids provides the basis for the ionic interaction and subsequent molecular recognition by specific receptor sites that results in the regulation of physiological or pathophysiological processes in the organism. In the development of new biologically active compounds that possess the ability to modulate these processes, compounds offering the same type of interactions are being designed. Thus, using a peptidomimetic design approach, glutamate and aspartate mimetics are incorporated into the structure of final biologically active compounds. This review covers different bioisosteric replacements of carboxylic acid alone, as well as mimetics of the whole amino acid structure. Amino acid analogs presented include those with different distances between anionic moieties, and analogs with additional functional groups that result in conformational restriction or alternative interaction sites. The article also provides an overview of different cyclic structures, including various cycloalkane, bicyclic and heterocyclic analogs, that lead to conformational restriction. Higher di- and tripeptide mimetics in which carboxylic acid functionality is incorporated into larger molecules are also reviewed. In addition to the mimetic structures presented, emphasis in this article is placed on their steric and electronic properties. These mimetics constitute a useful pool of fragments in the design of new biologically active compounds, particularly in the field of RGD mimetics and excitatory amino acid agonists and antagonists.
Stefanic
Peter
P
University of Ljubljana, Faculty of Pharmacy, 1000 Ljubljana, Slovenia.
Dolenc
Marija Sollner
MS
D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors; D001224:Aspartic Acid / Q000737:chemistry* / Q000378:metabolism*; D002264:Carboxylic Acids / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000737:chemistry* / Q000378:metabolism*; D018716:Molecular Mimicry; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D001224:Aspartic Acid; D018698:Glutamic Acid; C047981:arginyl-glycyl-aspartic acid; D000591:Amino Acid Isomerases; C062292:glutamate racemase