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Cyclo-Polyproline: Chameleonic All-Peptide Macrocycles With Induced-Fit Host-Guest Recognition
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DOI：10.1002/anie.8698780.png)
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Abstract
En 中文
We report the design, synthesis, and characterization of a novel class of all-peptide macrocycles, Cyclo-Polyprolines (CP). Exploiting the precision of Fmoc-based solid-phase peptide synthesis (SPPS) and head-to-tail macrocyclization, this platform grants unparalleled control over the macrocycle's primary sequence and secondary structure, offering a viable route toward exo-/endo-functionalization and addressing a bottleneck of traditional synthetic host macrocycles. The resulting CP scaffold is highly amphiphilic, exhibiting excellent solubility in both organic and aqueous media. Structural analysis via NMR spectroscopy and single-crystal x-ray diffraction reveals a distinct chameleonic character: the macrocycle shifts from an all-junctions-cis conformation in organic solvents to a predominantly all-junctions-trans isomer in water. We demonstrate that this transition is driven by a cooperative hydration effect, wherein water molecules stabilize the expanded framework through precise two-point hydrogen bonding. Demonstrating responsive host-guest capabilities, CP undergoes induced-fit isomerization to bind ligands, successfully forming, among other species, an all-peptide pseudo-rotaxane. This methodology establishes a robust platform for creating functionalized, proline-based hosts with significant potential in medicinal chemistry, drug delivery, and organocatalysis, thereby bridging the gap between supramolecular systems and enzyme mimetics.
Keywords:
cyclo-polyproline
host-guest systems
peptide-based macrocycles
peptide-based supramolecular chemistry
supramolecular chemistry
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