ABSTRACT
This paper reports a detailed conformational characterization in solution by 1H-NMR in H2O and DMSO-d6 and molecular modeling simulations of cyclic peptides containing the RGDDV pharmacophore and the RGDY(Me)R pharmacophore. These two pentapeptide sequences when properly constrained in cyclic peptides are low to sub-nanomolar inhibitors of integrin alpha(v)beta3. The peptides containing the RGDDY(Me)R sequence bind potently to integrin alphaIIb3 as well. The conformations found in H2O and in DMSO-d6 solutions are valuable for the design of peptidomimetics of these two pharmacophores. The structure-activity relationships of the RGDDV and RGDY(Me)R pharmacophores within cyclic peptides are discussed. Specifically, the orientation of surface-accessible chemical features on the ligand, such as hydrophobic, positive and negative ionizable groups, which are considered to be responsible for the desired biological activity, is focused on.
Subject(s)
Oligopeptides/chemistry , Peptides, Cyclic/chemistry , Protein Conformation , Receptors, Vitronectin/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Protein Binding , Receptors, Vitronectin/antagonists & inhibitorsABSTRACT
The cell adhesion domain, arginine-glycine-aspartic acid (RGD), has been incorporated into synthetic peptides to perform either of two modes of drug action, antagonist or agonist. Short, conformationally constrained peptides have been developed as antagonists for the platelet membrane glycoprotein complex, the integrin alpha IIb beta 3, using cell-based and integrin-based assays. In combination with a comparative molecular modeling study, these results have helped identify common conformational elements in the pharmacophore of this class of molecules. Peptides are presented that are highly potent, integrin specific, and that possess reduced pharmacological side effects. Also presented is the development of a peptide that modifies, noncovalently, the surfaces of a wide variety of synthetic materials used in medical implants. The agonist activity of [corrected] this molecule is evident from its ability to stimulate cell attachment on these surfaces. This is shown to translate into an in vivo activity of faster and more complete tissue integration, and a reduction in foreign body response.
Subject(s)
Cell Adhesion , Oligopeptides , Peptides/chemistry , Amino Acid Sequence , Animals , Drug Design , Humans , Integrins/antagonists & inhibitors , Integrins/physiology , Models, Molecular , Molecular Sequence Data , Peptides/chemical synthesis , Peptides/pharmacology , Platelet Aggregation/drug effects , Platelet Glycoprotein GPIIb-IIIa Complex , Structure-Activity RelationshipABSTRACT
It has been a quarter of a century since Merrifield's initial report on solid-phase peptide synthesis. The field has matured significantly in recent years with a better understanding of the underlying chemistry. This is reflected by new, milder orthogonal protection schemes and more efficient coupling methods, some of which have been incorporated into automated systems. Advances in purification, especially high performance liquid chromatography, have had a major impact. The efficacy of these improvements has been demonstrated by an impressive litany of applications to biological problems.
