Folding and self-assembly of biomacromolecules has inspired the development of discrete, non-natural oligomers that fold and/or self-assemble in a controlled manner. Though aromatic and aliphatic ...oligoamides remain unmatched for structural diversity and synthetic versatility, oligomers based on amide bond surrogates, such as urea backbones, also demonstrated a propensity for folding and self-assembly. In this Perspective, we review the advances in the design of oligomeric aromatic and aliphatic urea sequences (essentially
N
,
N
′-linked) that fold and/or self-assemble. Whenever applicable, the relationship between structure and function will be highlighted.
Aromatic and aliphatic urea-based oligomers have been designed to fold and/or self-assemble. Structural insight provides a basis for the elaboration of molecules with function.
Peptides have gained so much attention in the last decade that they are now part of the main strategies, with small molecules and biologics, for developing new medicines. Despite substantial ...progress, the successful development of peptides as drugs still requires a number of limitations to be addressed, including short in vivo half-lives and poor membrane permeability. Here, we describe the use of oligourea foldamers as tool to improve the pharmaceutical properties of GLP-1, a 31 amino acid peptide hormone involved in metabolism and glycemic control. Our strategy consists in replacing four consecutive amino acids of GLP-1 by three consecutive ureido residues by capitalizing on the structural resemblance of oligourea and α-peptide helices. The efficacy of the approach is demonstrated with three GLP-1-oligourea hybrids showing prolonged activity in vivo. Our findings should enable the use of oligoureas in other peptides to improve their pharmaceutical properties and may provide new therapeutic applications.
Anion binding properties of neutral helical foldamers consisting of urea type units in their backbone have been investigated. 1H NMR titration studies in various organic solvents including DMSO ...suggest that the interaction between aliphatic oligoureas and anions (CH3COO−, H2PO4−, Cl−) is site‐specific, as it largely involves the urea NHs located at the terminal end of the helix (positive pole of the helix), which do not participate to the helical intramolecular hydrogen‐bonding network. This mode of binding parallels that found in proteins in which anion‐binding sites are frequently found at the N‐terminus of an α‐helix. 1H NMR studies suggest that the helix of oligoureas remains largely folded upon anion binding, even in the presence of a large excess of the anion. This study points to potentially useful applications of oligourea helices for the selective recognition of small guest molecules.
Free to interact! The four backbone urea NHs located at the positive pole of homo‐oligourea helices are ideally preorganized to interact with anionic guests. 1H NMR titration studies with various anions reveal that binding to oligoureas is site‐selective and does not cause a helix unfolding. This anion‐ binding mode is reminiscent of that observed in proteins in which anion‐ binding sites are frequently found at the N‐terminus of an α‐helix.
Cell-penetrating foldamers (CPFs) have recently shown promise as efficient and safe nucleic acid delivery systems. However, the application of CPFs to siRNA transport remains scarce. Here, we report ...helical CPFs tailored with specific end-groups (pyridylthio- or
n
-octyl-ureas) as effective molecular systems in combination with helper lipids to intracellularly deliver biologically-relevant siRNA.
Tailored end-group modifications and the formulation of cell-penetrating urea-based foldamers enable efficient siRNA delivery into cells.
Substantial progress has been made toward the development of metal-free catalysts of enantioselective transformations, yet the discovery of organic catalysts effective at low catalyst loadings ...remains a major challenge. Here we report a novel synergistic catalyst combination system consisting of a peptide-inspired chiral helical (thio)urea oligomer and a simple tertiary amine that is able to promote the Michael reaction between enolizable carbonyl compounds and nitroolefins with excellent enantioselectivities at exceptionally low (1/10 000) chiral catalyst/substrate molar ratios. In addition to high selectivity, which correlates strongly with helix folding, the system we report here is also highly amenable to optimization, as each of its components can be fine-tuned separately to increase reaction rates and/or selectivities. The predictability of the foldamer secondary structure coupled to the high level of control over the primary sequence results in a system with significant potential for future catalyst design.
The design and construction of biomimetic self-assembling systems is a challenging yet potentially highly rewarding endeavour that contributes to the development of new biomaterials, catalysts, ...drug-delivery systems and tools for the manipulation of biological processes. Significant progress has been achieved by engineering self-assembling DNA-, protein- and peptide-based building units. However, the design of entirely new, completely non-natural folded architectures that resemble biopolymers ('foldamers') and have the ability to self-assemble into atomically precise nanostructures in aqueous conditions has proved exceptionally challenging. Here we report the modular design, formation and structural elucidation at the atomic level of a series of diverse quaternary arrangements formed by the self-assembly of short amphiphilic α-helicomimetic foldamers that bear proteinaceous side chains. We show that the final quaternary assembly can be controlled at the sequence level, which permits the programmed formation of either discrete helical bundles that contain isolated cavities or pH-responsive water-filled channels with controllable pore diameters.
Synthetic foldamers Guichard, Gilles; Huc, Ivan
Chemical communications (Cambridge, England),
01/2011, Letnik:
47, Številka:
21
Journal Article
Recenzirano
Foldamers are artificial folded molecular architectures inspired by the structures and functions of biopolymers. This highlight focuses on important developments concerning foldamers produced by ...chemical synthesis and on the perspectives that these new self-organized molecular scaffolds offer. Progress in the field has led to synthetic objects that resemble small proteins in terms of size and complexity yet that may not contain any α-amino acids. Foldamers have introduced new tools and concepts to develop biologically active substances, synthetic receptors and novel materials.
APO2L/TRAIL (TNF-related apoptosis-inducing ligand) induces death of tumor cells through two agonist receptors, TRAIL-R1 and TRAIL-R2. We demonstrate here that N-linked glycosylation (N-glyc) plays ...also an important regulatory role for TRAIL-R1-mediated and mouse TRAIL receptor (mTRAIL-R)-mediated apoptosis, but not for TRAIL-R2, which is devoid of N-glycans. Cells expressing N-glyc-defective mutants of TRAIL-R1 and mouse TRAIL-R were less sensitive to TRAIL than their wild-type counterparts. Defective apoptotic signaling by N-glyc-deficient TRAIL receptors was associated with lower TRAIL receptor aggregation and reduced DISC formation, but not with reduced TRAIL-binding affinity. Our results also indicate that TRAIL receptor N-glyc impacts immune evasion strategies. The cytomegalovirus (CMV) UL141 protein, which restricts cell-surface expression of human TRAIL death receptors, binds with significant higher affinity TRAIL-R1 lacking N-glyc, suggesting that this sugar modification may have evolved as a counterstrategy to prevent receptor inhibition by UL141. Altogether our findings demonstrate that N-glyc of TRAIL-R1 promotes TRAIL signaling and restricts virus-mediated inhibition.
The bacterial DNA sliding clamp (SC), or replication processivity factor, is a promising target for the development of novel antibiotics. We report a structure–activity relationship study of a new ...series of peptides interacting within the Escherichia coli SC ( Ec SC) binding pocket. Various modifications were explored including N-alkylation of the peptide bonds, extension of the N-terminal moiety, and introduction of hydrophobic and constrained residues at the C-terminus. In each category, single modifications were identified that increased affinity to Ec SC. A combination of such modifications yielded in several cases to a substantially increased affinity compared to the parent peptides with K d in the range of 30–80 nM. X-ray structure analysis of 11 peptide/ Ec SC co-crystals revealed new interactions at the peptide–protein interface (i.e., stacking interactions, hydrogen bonds, and hydrophobic contacts) that can account for the improved binding. Several compounds among the best binders were also found to be more effective in inhibiting SC-dependent DNA synthesis.
There is an urgent need to develop new therapeutic strategies to fight the emergence of multidrug resistant bacteria. Many antimicrobial peptides (AMPs) have been identified and characterized, but ...clinical translation has been limited partly due to their structural instability and degradability in physiological environments. The use of unnatural backbones leading to foldamers can generate peptidomimetics with improved properties and conformational stability. We recently reported the successful design of urea-based eukaryotic cell-penetrating foldamers (CPFs). Since cell-penetrating peptides and AMPs generally share many common features, we prepared new sequences derived from CPFs by varying the distribution of histidine- and arginine-type residues at the surface of the oligourea helix, and evaluated their activity on both Gram-positive and Gram-negative bacteria as well as on fungi. In addition, we prepared and tested new amphiphilic block cofoldamers consisting of an oligourea and a peptide segment whereby polar and charged residues are located in the peptide segment and more hydrophobic residues in the oligourea segment. Several foldamer sequences were found to display potent antibacterial activities even in the presence of 50% serum. Importantly, we show that these urea-based foldamers also possess promising antifungal properties.
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