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A simple strategy is proposed to assess the propensity of a given monomer to follow or not follow a particular helical scheme and to study helix reversal phenomena within helical oligomers. It consists of placing a monomer having a low helix propensity between two conformationally stable helical segments. Helix reversion then occurs preferentially at the site of this monomer, leading to the formation of isomers having P (right-handed) or M (left-handed) helicities at each of the two helical segments. The proportion between the P-P/M-M and P-M isomers is indicative of the stereochemical relations between the inserted monomer and the helical frame. Thus, xylylene or carboxylic acid anhydride spacers have been introduced between two helical oligoamides of 8-amino-2-quinolinecarboxylic acid. Both these spacers presumably lack some of the structural features that confer quinoline units with a high helix propensity. Only one species is observed in solution in the case of an anhydride spacer. This species was shown by x-ray crystallography to be a racemic mixture of P-P and M-M helices. Unexpectedly, the anhydride is consistently incorporated within helical oligoamides. For the xylylene spacer, the P-P/M-M racemate and P-M meso compound are in equal proportions in chloroform, showing that this spacer does not have a propensity to adopt any helical conformation in this solvent. However, the equilibria between the various isomers are shifted in toluene, where one species largely prevails. This species was shown by x-ray crystallography to be the P-P/M-M racemate. Molecular dynamics simulations are consistent with these solution data. conformation analysis | folding | helices

Chiral groups attached to the end of quinoline-derived oligoamide foldamers give rise to chiral helical induction in solution. The right-handed or left-handed helical sense favored by the terminal chiral group could be determined unambiguously using X-ray crystallography.

A new strategy is proposed to control the relative orientation of two folded helical oligomers in such a way that they diverge from an aromatic linker and have opposite helical handedness. The concept is validated using the helical conformations of oligoamides of 8-amino-2-quinolinecarboxylic acids.

Efficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence‐based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein–protein interactions (PPI). However, the precise design of such mimics is currently limited by the lack of structural information on how these foldamers adapt to protein surfaces. We report a collection of X‐ray structures of peptide–oligourea hybrids in complex with ubiquitin ligase MDM2 and vitamin D receptor and show how such hybrid oligomers can be designed to bind with high affinity to protein targets. This work should enable the generation of more effective foldamer‐based disruptors of PPIs in the context of peptide lead optimization. [ABSTRACT FROM AUTHOR]

Short peptides are induced into [alpha]-helix conformations in water through enclathration to an artificial hydrophobic cavity. Peptides with two aromatic residues have displayed high affinity for the host and these intermolecular aromatic-aromatic interactions have driven the helical folding of short peptides.

The discovery of improved and remarkably regioselective electrophilic substitutions in helically folded aromatic oligoamides is described. The reaction selectivity depends on the presence of substituents that are remote from the reaction site.

The synthesis of various 1,8-diaza-4,5-dialkoxy-2,7-anthracene dicarboxylic acid derivatives and their incorporation into cyclic and helically folded aromatic oligoamides are described. Longer, noncyclic oligoamides composed of one or two diaza-anthracene units have adopted helical conformations that have existed preferentially as double helical dimers.

A description of the design and synthesis of new amphipathic helical oligoamides based on quinoline-derived amino acids having either hydrophobic or cationic side chains is presented. Amphipathic helices are versatile targets to of investigation in view of their importance in a variety of biological processes, and the unique structure and properties of the quinoline-derived oligoamides might allow new structure-activity relationships to be developed.

The reasons for the handedness of helical polymers or oligomers that has attracted widespread interest are provided. Solution state-solid state equilibrium provides an original means to control helical handedness in synthetic oligomers.

Oligoamides of 2,6-diaminopyridine and 2,6-pyridinedicarboxylic acid (AOAS) fold into stable single helices and hybridize into double-helical dimes in solution and in the solid. Hybridization of N-oxide oligomers proceeds in a similar manner as that for the native strands extending the register of structures capable of forming double-helical dimmers and opening the way toward cross-hybridization experiments.

In the search of molecules that could recognize sizeable areas of protein surfaces, a series of ten helical aromatic oligoamide foldamers was synthesized on solid phase. The foldamers comprise three to five monomers carrying various proteinogenic side chains, and exist as racemic mixtures of interconverting right-handed and left-handed helices. Functionalization of the foldamers by a nanomolar ligand of human carbonic anhydrase II (HCA) ensured that they would be held in close proximity to the protein surface. Foldamer-protein interactions were screened by circular dichroism (CD). One foldamer displayed intense CD bands indicating that a preferred helix handedness is induced upon interacting with the protein surface. The crystal structure of the complex between this foldamer and HCA could be resolved at 2.1 Å resolution and revealed a number of unanticipated protein-foldamer, foldamer-foldamer, and protein-protein interactions. [ABSTRACT FROM AUTHOR]

Inducing the handedness of helical polymers or oligomers has attracted widespread interest because of its possible applications in optical devices or data storage and also because of its relevance to chiral amplification as it may have occurred at the early stages of life. Helical/nonhelical transitions and even inversion of helical chirality have been achieved upon changing solvent polarity or temperature, binding of chiral counterions, binding of chiral or nonchiral neutral guests molecules, protonation, irradiation using unpolarized or circularly polarized light, or electrochemical inputs. It is now reported that solution state-solid state equilibrium provides an original means to control helical handedness in synthetic oligomers.

Oligomers designed to form a helix-turn-helix super-secondary structure have been prepared by covalently bridging aliphatic oligourea foldamer helices with either rigid aromatic or more flexible aliphatic spacers. The relative helix orientation in these dimers was investigated at high resolution using X-ray diffraction analysis. In several cases, racemic crystallography was used to facilitate crystallization and structure determination. All structures were solved by direct methods. Well-defined parallel helical hairpin motifs were observed in all cases when 4,4'-methylene diphenyl diisocyanate was employed as a dimerizing agent, irrespective of primary sequence and chain length., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Efficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence-based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein-protein interactions (PPI). However, the precise design of such mimics is currently limited by the lack of structural information on how these foldamers adapt to protein surfaces. We report a collection of X-ray structures of peptide-oligourea hybrids in complex with ubiquitin ligase MDM2 and vitamin D receptor and show how such hybrid oligomers can be designed to bind with high affinity to protein targets. This work should enable the generation of more effective foldamer-based disruptors of PPIs in the context of peptide lead optimization., (© 2020 Wiley-VCH GmbH.)

The unambiguous elucidation of a new folded structure in solution may prove to be a very challenging task. The NMR protocols developed for solving the solution structures of alpha-peptides have been applied to aliphatic beta- and gamma-peptides but are not directly applicable to aromatic oligomers. In particular, the string of spin systems in an aromatic sequence cannot be reconstituted solely from correlations between protons. For aromatic oligomers, it is shown that the assignment of a large part of the 13C NMR spectrum through HMBC and HSQC experiments allows to unambiguously assign proton NMR spectra and in turn to interpret NOE correlations. This has been implemented both with quinoline- and pyridine-derived oligoamide foldamers, and should be applicable to a wide range of oligomers including various combinations of monomers. The NOE correlations allow the unambiguous solution structure elucidation of helical conformations of oligoamides derived from pyridine and quinoline monomers showing that, in these series, the solution structures correspond very well to the structures observed in the solid state.