Conformational and Topographical Considerations in Designing Agonist Peptidomimetics from Peptide Leads

Abstract

The design of peptidomimetic ligands with agonist biological activities in vitro and in vivo has been challenging. Lofty goals have been set for this research including high potency, high receptor type selectivity, high stability in vitro and in vivo, and high efficacy in vitro and in vivo for agonists. A systematic stepwise strategy has been developed to accomplish these goals. These include determining the primary amino acid side chain residues required for molecular recognition and, in the case of agonist activity, those required for information transduction. In addition to determining the preferred backbone conformation which can serve as a template for the bioactive conformation (an alpha-helix, beta-turn, beta-sheet, etc.), a strategy has been developed to examine and determine the preferred side chain conformations in chi space (chi1, chi2, etc.). These include specific covalent and non-covalent constraints which can place the constrained side chains at highly preferred gauche (-), or gauche (+), or trans conformations. Examples are provided that illustrate this methodology and provide insight into the topographical requirements for ligand receptor interactions. Often, at this juncture one can obtain a quite precise 3D pharmacophore for the ligand, as well as high stability to agonist biodegradation and good bioavailability including the ability to cross membrane barriers. If a non-peptide ligand is desired, efforts are in progress to develop templates, and aspects of conformational design that permit assembling of all components necessary for molecular recognition and transduction. Here the proper choice of template that can place the key side chain residue in 3D space is still difficult, and thus only partial success has been achieved in terms of potent and selective ligands. A few of these approaches are presented and discussed in some detail.

Coupling to Polymeric Scaffolds Stabilizes Biofunctional Peptides for Intracellular Applications

“…Therefore, peptides provide a highly valuable repertoire of molecular interactors, both in basic and applied biomedical research (Cooper and Waters, 2005). In the past years, numerous peptides have been approved as drugs (Hruby and Balse, 2000;Bray, 2003;Leader et al, 2008). Nevertheless, the intracellular applicability of peptides is still limited.…”

Directing the Immune Response to Carbohydrate Antigens

“…Whereas peptide library screening has led to the identification of a variety of peptide mimetics of carbohydrate antigens (14,15), concepts described for the design of small molecules may apply equally well to the design of mimetics of carbohydrate antigens (16,17). To further facilitate concepts for a structure-assisted vaccine design, we considered, as a model system, small molecule interactions with concanavalin A (ConA).…”

Application of a new methodology for the synthesis and resolution of a ß-(thien-2-yl) proline with the 7-azanorbornane skeleton

“…Methyl 1-benzamido-4-oxo-t-2-(thien-2-yl)cyclohexane-r-1-carboxylate (rac-4). A solution of methyl 1-benzamido-4-oxo-t-6-(thien-2-yl)-2-cyclohexene-r-1-carboxylate, rac-3 (3 g, 8.5 mmol), in dichloromethane (30 mL) was hydrogenated at atmospheric pressure for 24 h at 30°C using 20% Pd(OH) 2 59 (m, 3H). 13 C-NMR (CDCl 3 ) δ: 207.…”

“…13 C-NMR (CDCl 3 ) δ 172. 2,168.5,140.8,134.6,131.8,128.6,127.5,126.8,125.7,125.1,76.5,64.1,52.5,39.6,38.7,33.4,25.9,25.0. Anal.…”

“…1 Furthermore, it has become a useful tool for the elucidation of biologically active conformations 1a,2 by providing information about the spatial requirements for optimal interaction with receptors. 2,3 Several β-substituted prolines ( Figure 1) have been synthesized as amino acid chimeras in which the functional groups of the amino acid side-chain are combined with the conformational restrictions characteristic of the cyclic amino acid residue. 4 Replacement of the natural amino acids in peptides with such proline-α-amino acid chimeras has led to better understanding of the bioactive conformations of cholecystokinin, 5 angiotensin II, 6 bradykinin, 7 and opioid peptides.…”