Figure 2 - uploaded by Luigi F. Di Costanzo
Content may be subject to copyright.
(a) Prospective macrocyclic hexapyrrolinones 2 and 3; b) Stereoview of the lowest energy conformation of 2 derived via Monte Carlo conformational analysis.
Source publication
The design, synthesis, and structural analysis of two macrocyclic D,L-alternating hexapyrrolinones have been achieved. These cyclic peptide mimics adopt a flat, hexagonal conformation, stabilized by intramolecular hydrogen bonding between adjacent pyrrolinone rings. Extensive NMR studies and X-ray analysis reveal, respectively, that the macrocyclic...
Contexts in source publication
Context 1
... self-assemble into nanotubes.9 Pleasingly, Monte Carlo conformational searches10 for 2 predicted that the low energy conformations would possess a flat, hexagonal conformation (Figure 2b), in agreement with previous structural analysis of the acyclic heterochiral pyrrolinones such as (−)-1. ...
Context 2
... self-assemble into nanotubes.9 Pleasingly, Monte Carlo conformational searches10 for 2 predicted that the low energy conformations would possess a flat, hexagonal conformation (Figure 2b), in agreement with previous structural analysis of the acyclic heterochiral pyrrolinones such as (−)-1. ...
Citations
A new approach to non-covalent peptide-based nanotubular or rod-like structures is presented, whereby the monomeric units are preorganised into a β-strand geometry that templates the formation of an extended and unusual parallel β-sheet rod-like structure. The conformational constraint is introduced by Huisgen cycloaddition to give a triazole-based macrocycle, with the resulting self-assembled structures stabilized by a well-defined series of intermolecular hydrogen bonds.
Peptidomimetic scaffolds designed to stabilize biologically relevant secondary structures play a key role in ligand-based drug design. Approaches aimed at stabilizing extended peptide conformations hold particular promise for targeting β-strand and β-sheet interactions. An understanding of how specific constraints impact extended backbone conformations is needed to expand their potential utility and to inform the design of novel templates. This chapter describes peptide orthotic and prosthetic approaches toward β-strand stabilization using heterocyclic motifs. Syntheses and conformational analyses are described for selected extended peptide surrogates suitable for incorporation into native sequences.
Among the greatest challenges in the field of microporous solids is the development of “smart” materials, displaying environment-triggered property tuning. These could be used both in traditional and new applications of microporous materials. In this context, supramolecular peptide-based solids have recently emerged as interesting alternatives to standard microporous solids, such as zeolites and carbon molecular sieves. They possess framework and conformational flexibility, are kinetically stable and reasonably thermally resistant. Important properties such as pore size and inner wall chemistry can be controlled through appropriate chemical modification of the peptide molecules. Peptide-based porous solids have permanent microporosity, often with molecularly sized cavities created by removal of co-crystallised solvent. Some have already been successfully tested as adsorbents and permselective materials, confirming their potential. This review covers the identification, synthesis, characterization techniques and properties of peptide-based microporous solids, discussing their most unique functionalities.
Many "new generation" peptidomimetics are designed to present amino acid side chains only; they do not have structural features that resemble peptide main chains. These types of molecules have frequently been presented in the literature as mimics of specific secondary structures. However, many "side-chain only" peptidomimetics do not rest in single conformational states, but exist in a limited number of freely interconverting forms. These different conformations may resemble different secondary structures, so referring to them as, for instance, turn- or helical-mimics understates the ways they could adapt to various binding situations. Sets of scaffolds that can be used to mimic aspects of nearly every secondary structure, i.e. universal peptidomimetics, can be constructed. These may assume a privileged place in library design, particularly in high throughput screening for pharmacological probes for which binding conformations, or even the target itself, is unknown at the time the library is designed (critical review, 101 references).
This paper concerns peptidomimetic scaffolds that can present side chains in conformations resembling those of amino acids in secondary structures without incurring excessive entropic or enthalpic penalties. Compounds of this type are referred to here as minimalist mimics. The core hypothesis of this paper is that small sets of such scaffolds can be designed to analogue local pairs of amino acids (including noncontiguous ones) in any secondary structure; i.e., they are universal peptidomimetics. To illustrate this concept, we designed a set of four peptidomimetic scaffolds. Libraries based on them were made bearing side chains corresponding to many of the protein-derived amino acids. Modeling experiments were performed to give an indication of kinetic and thermodynamic accessibilities of conformations that can mimic secondary structures. Together, peptidomimetics based on these four scaffolds can adopt conformations that resemble almost any combination of local amino acid side chains in any secondary structure. Universal peptidomimetics of this kind are likely to be most useful in the design of libraries for high-throughput screening against diverse targets. Consequently, data arising from submission of these molecules to the NIH Molecular Libraries Small Molecule Repository (MLSMR) are outlined.
Peptides and proteins, evolved by nature to perform vital biological functions, would constitute ideal candidates for therapeutic intervention were it not for their generally poor pharmacokinetic profiles. Nonpeptide peptidomimetics have thus been pursued because they might overcome these limitations while maintaining both the potency and selectivity of the parent peptide or protein. Since the late 1980s, we have sought to design, synthesize, and evaluate a novel, proteolytically stable nonpeptide peptidomimetic scaffold consisting of a repeating structural unit amenable to iterative construction; a primary concern is maintaining both the appropriate peptide-like side-chains and requisite hydrogen bonding. In this Account, we detail how efforts in the Smith−Hirschmann laboratories culminated in the identification of the 3,5-linked polypyrrolinone scaffold.
