Untitled

Abstract

Examples of reverse turns as recognition motifs in biological systems can be found in high-resolution crystal structures of antibody-peptide complexes. Development of peptidomimetics is often based on replacing the amide backbone of peptides by sugar rings, steroids, benzodiazepines, or other hetero- and carbocycles. In this approach, the chemical scaffold of the peptide backbone can be replaced while retaining activity as long as the pharmacophoric groups of the peptide side chains stay in relatively the same place; in other words, similar functional groups must overlap in space for interaction with critical receptor sites. This study evaluates the potential of metal complexes of chiral pentaazacrowns (PAC) derived by reduction of cyclic pentapeptides as beta-turn mimetics. Due to the limited flexibility of the pendant chiral side groups in these metal complexes, one can potentially elicit information about the receptor-bound conformation from their binding affinities. 11 PAC crystal structures with different substitution patterns complexed with 3 different metals (Mn, Fe, Cd) as a prototypical database of potential side-chain orientations. Complexation with different metals induces subtle differences in the conformations of a particular azacrown scaffold. The lack of parameterization of transition metals for force field calculations precludes a thorough theoretical study. Thus, this study utilizes a simple geometrical comparison between the experimental data for crystalline PAC complexes and the side-chain orientations seen in classic beta-turns. The FOUNDATION program was used to overlap the Calpha-Cbeta vectors of the corresponding ideal beta-turn side-chains to all possible leaving groups of the PAC complexes. When comparing the relative orientations of the chiral side chains, a strong overlap of the bonds (between about 0.1 A to about 0.5 A RMS for 3 residues and up to about 1 A RMS for 4 residues) was observed for many of the molecules. Such metal complexes may lack complete peptidomimetic activity due to the lack of spatial overlap of all four side-chain residues, however, if only three peptide side chains are needed for receptor recognition and/or binding, the metal complexes should show biological activity.

Development of small molecules designed to modulate protein–protein interactions

“…D-Glucose, L-glucose and L-mannose structural isomers were synthesized and displayed different subtype selectivity for somatostatin receptors [149]. Marshall and his co-workers [150] showed that metal complexes of chiral pentaazacrowns (MAC), derived by reduction of cyclic pentapeptides, fixed side chains in orientations comparable to those of ideal b-turns. The minor changes in side chain orientation with different metals offer an opportunity for subtle optimization of binding specificity not available through conventional organic chemistry.…”

Organometallics as Structural Scaffolds for Enzyme Inhibitor Design

“…In contrast to many polyoxometallates, this cluster has been demonstrated to be stable under physiological conditions. Marshall and coworkers proposed the utilization of metal complexes of chiral azacrowns (MACs) as a strategy to influence the conformation of these macrocycles and to fix the chiral side chains in orientations comparable with those of peptidic b-turns [18][19][20]. For example, the MAC complex 3 was proposed to serve as a nonpeptidic inhibitor of amylase by mimicking the active reversed b-turn sequence Trp18-Arg19-Tyr20 of the proteinaceous amylase inhibitor tendamistat (Fig.…”

c[D‐pro‐Pro‐D‐pro‐N‐methyl‐Ala] adopts a rigid conformation that serves as a scaffold to mimic reverse‐turns

“…[6][7][8]11 Two methods used to nucleate reverse-turn structures incorporate a sequence of either pro-Pro or Pro-pro at the i+1 and i+2 positions [12][13][14] of the turn, or use small cyclic peptides either cyclized through side chains or head-totail. 5,7,15,16 Cyclic peptides are widely investigated for therapeutic use due to their rigid scaffold and bioavailability. 17 Cyclic peptides, such as h-Defensins, naturally occur in many organisms and have a broad range of activity, acting as antibiotics or antivirals for HIV-1, herpes simplex, or influenza A viruses.…”