Jul 2026· Organic and biomolecular chemistry· Vol 24, pp. 6992 - 6998· 0 citations
Medicine
Abstract
Mediation of protein–protein interactions with molecules that bind strongly and selectively to one of the partners at the protein interface is a promising therapeutic strategy for myriad diseases. One such approach is the rational design of non-peptidic scaffolds that reproduce the display of amino acid side chains from one face of a secondary structural element. We have previously disclosed proof-of principle syntheses of β-strand mimetics composed of alternating (hetero)aromatic and cyclic urea units, conformationally preorganised through dipolar repulsion in organic solvents, that are in good agreement with the i, i + 2, and i + 4 side-chain vectors of a canonical strand. Here we demonstrate sequence diversity of the approach through the incorporation of hydrophobic and hydrophilic side-chain mimics via an improved synthetic route. The scaffold is conformationally preorganised for target binding in aqueous media including buffer, is readily soluble, and thus is suitable for elaboration and deployment against specific protein targets.
G-quadruplexes (G4s) are noncanonical nucleic acid structures involved in the regulation of key biological processes and represent attractive targets for therapeutic intervention. In this study, we report the design, synthesis, and biophysical evaluation of a new family of water-soluble heptacyclic oligo-heteroaryl ligands tailored for G4 recognition. The synthetic route, based on a modular and convergent approach, enables late-stage functionalization and overcomes common limitations of macrocyclic scaffolds such as low yields and poor tractability. The new compounds incorporate 1,2,4-oxadiazole and 1,2,3-triazole units as bioisosteric replacements for oxazole and systematically vary the nature of the central atoms (C vs N) and pendant groups to investigate their effect on G4 binding. All derivatives displayed high aqueous solubility under physiological conditions and selective stabilization of G4 structures, particularly the parallel LTR-IV motif. Biophysical studies and docking calculations indicate that these ligands operate primarily through groove-binding interactions. Notably, no substantial differences were observed between nitrogen- and carbon-substituted analogues, suggesting a conserved binding profile across the series. These findings identify a versatile class of G4 binders with favorable solubility and structural tunability, laying the groundwork for the development of functionalized derivatives for chemical biology and therapeutic applications.
Giorgia Fracchioni, A. M. Caramiello, M. Nadai et al.· ACS Omega· 0 citations
Peptide-based materials have enormous potential for applications including therapeutics, sensing, catalysis, and flexible electronics. Recent material discovery screenings through peptide sequence space have identified a class of amphiphilic heme-containing peptides that self-assemble at the nanoscale while efficiently sequestering heme as a prerequisite for electron transfer. However, the assemblies are remarkably sensitive to changes in peptide sequence, even at the single-residue level, impacting heme uptake, aggregate characteristics, and stability. In a combined experimental and molecular simulation study, we examine the interplay between hydrophobicity and charge–charge repulsion on the heme uptake performance and physicochemical characteristics of the assemblies of representative peptides, ExL4–xL5HL6 for x = 2, 3, 4. We find that membrane permeability and compressibility are beneficial for heme uptake, while striking a balance with the overall stability of the assembly. This work highlights the sensitivity of material performance within peptide design space while providing insight into the compromise that must be struck between competing characteristics.
Jesse L. Prelesnik, A. P. Lau, Nathan C. Laud et al.· Journal of the American Chem...· 0 citations
Macrocyclic peptides are attracting attention as a promising therapeutic modality for addressing intracellular targets that are traditionally difficult to address with conventional small molecules or antibodies. In this study, we present the chemical optimization process behind the development of AUBE00 (AP7400, compound 30), a KRAS-selective inhibitor based on a scaffold similar to LUNA18, an orally bioavailable macrocyclic peptide RAS inhibitor. Achieving KRAS isoform selectivity is exceptionally challenging due to the nearly identical backbone structures of KRAS, HRAS, and NRAS (Cα RMSD < 1.1 Å). The success of this study relied on two critical factors: (1) achieving conformational control of the flexible N-alkyl group through a bridging structure linked to the adjacent side chain, which enabled the exploitation of subtle interaction energy differences among the isoforms; and (2) overcoming the trade-off between improved KRAS selectivity and reduced permeability associated with P-glycoprotein (P-gp) substrate liability by employing a modified Caco-2 membrane permeability assay to recover oral bioavailability. Our results demonstrate that a conformational rigidification through a bridged scaffold, implemented while preserving membrane permeability, is a highly effective strategy for achieving isoform selectivity. This study establishes a generalizable design principle for orally bioavailable macrocyclic peptides targeting intracellular proteins that require mutation or isoform selectivity.
M. Kage, Hatsuo Kawada, Koji Takano et al.· Journal of the American Chem...· 0 citations
Peptoids, or N-substituted glycine oligomers, are a unique class of biomimetic foldamers. Peptoid oligomers are indeed capable of adopting well-defined ordered structures despite their intrinsic flexibility, which is primarily attributable to the cis/trans isomerism of the main chain tertiary amide bonds. Controlling the geometry of the amides can lead to a diversity of diastereomeric structures. Here, we report for the first time that peptoid hexamers can adopt a unique looplike structure with a cis-cis-trans-cis-cis arrangement of the backbone amides. We found that a neutral zwitterionic state is necessary for the formation and stabilization of this structure by ion-pair interaction between the positively and negatively charged N- and C-termini. The novel loop structure exhibits a remarkable stability in chloroform and acetonitrile. In methanol, the oligomers adopt the more common polyproline type I (PPI) helical conformation. A comprehensive NMR solution structure determination was carried out on a hexamer containing four central (S)-N-(1-phenylethyl)glycines (Nspe) and two N-tert-butylglycines at the terminal ends. Our study reveals a distinct circular dichroism (CD) fingerprint for loop-shaped peptoids containing chiral aromatic Nspe monomers. The structure in solution was corroborated by a high-resolution crystal structure. Furthermore, we provide evidence that substituting the aromatic Nspe units with aliphatic (S)-N-(1-cyclohexylethyl)glycines (Nsch) or (S)-N-(1-tert-butylethyl)glycines (Nstbe) monomers does not impact loop folding processes. Finally, we demonstrate a reversible conformational switch between the loop structure and the PPI helix in response to external acid-base stimuli. This reversible stimulus-driven structural reorganization opens up opportunities to develop on/off switchable systems for next-generation smart applications.
Zacharie Bordas, Baptiste Legrand, Souleymane Sarr et al.· Journal of the American Chem...· 0 citations
Macrocyclic peptides and peptidomimetics (MPPs) have emerged as a powerful therapeutic class in peptide-based drug discovery, uniquely positioned to modulate challenging protein-protein interactions (PPIs). While dysregulated PPIs drive diverse human pathologies, including cancer, metabolic disorders, neurodegenerative proteinopathies, inflammatory conditions, and microbial infections, targeting them remains difficult. Traditional small molecules lack the surface area to bind large, flat PPI interfaces, whereas linear peptides suffer from rapid proteolytic degradation and poor cell permeability. MPPs overcome these limitations by bridging the gap between small molecules and biologics. Their cyclic architecture provides conformational rigidity minimizing entropic penalties and maximizing binding affinity and selectivity. This structural pre-organization also enhances metabolic robustness, protease resistance, and cellular permeability. This review comprehensively examines the biological significance of PPIs in human disease and details how MPPs effectively modulate historically undruggable targets. We highlight current synthetic strategies, peptide engineering platforms, and the clinical and preclinical status of leading MPP candidates, while weighing their operational advantages and limitations. Finally, we analyze the contemporary market trajectory and emerging commercial opportunities, positioning MPPs as next-generation, PPI-targeting therapeutics.
Peptide stapling exerts profound effects on key peptide properties, including metabolic stability, cell membrane permeability, and conformational constraint. Herein, we report a mild and efficient 2,4-dichloro-1,3,5-triazine-mediated stapling strategy for the selective cross-linking of lysine side-chain amines. This approach furnishes macrocyclic peptides of varying ring sizes. This method features broad functional group compatibility with most natural amino acid residues (His, Trp, Arg, Tyr, Ser and Thr), as well as N-terminal α-amino and C-terminal carboxylate moieties, whereas cysteine is not tolerated in this transformation. For the representative stapled macrocyclic peptides, the 1,3,5-triazine bridge significantly enhanced proteolytic stability, membrane permeability and helical propensity, and potentiated their antiproliferative activity against multiple cancer cell lines.
