The chemical synthesis of peptide-based [1]rotaxanes (lasso peptides) was achieved by [2]rotaxane formation followed by two chemoselective ligation reactions. Our approach enabled incorporation of various peptide sequences into a common rotaxane structure. The synthetic lasso peptides were characterized by NMR, chromatography, and partial degradation by proteases. A linear peptide epitope grafted onto the rotaxane scaffold showed significantly improved proteolytic stability.
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http://dx.doi.org/10.1039/c7sc00021a | DOI Listing |
Biomacromolecules
June 2024
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
Rotaxane cross-linkers enhance the toughness of the resulting rotaxane cross-linked polymers through a stress dispersion effect, which is attributed to the mobility of the interlocked structure. To date, the compositional diversity of rotaxane cross-linkers has been limited, and the poor compatibility of these cross-linkers with peptides and proteins has made their use in such materials challenging. The synthesis of a rotaxane composed of peptides may result in a biodegradable cross-linker that is compatible with peptides and proteins, allowing the fortification of polypeptides and proteins and ultimately leading to the development of innovative materials that possess excellent mechanical properties and biodegradability.
View Article and Find Full Text PDFACS Chem Biol
January 2024
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States.
Lasso peptides are a structurally distinct class of biologically active natural products defined by their short sequences with impressively interlocked tertiary structures. Their characteristic peptide [1]rotaxane motif confers marked proteolytic and thermal resiliency, and reports on their diverse biological functions have been credited to their exceptional sequence variability. Because of these unique properties, taken together with improved technologies for their biosynthetic production, lasso peptides are emerging as a designable scaffold for peptide-based therapeutic discovery and development.
View Article and Find Full Text PDFCommun Chem
June 2023
University of Zurich, Department of Chemistry, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Dual-modality imaging agents featuring both a radioactive complex for positron emission tomography (PET) and a fluorophore for optical fluorescence imaging (OFI) are crucial tools for reinforcing clinical diagnosis and intraoperative surgeries. We report the synthesis and characterisation of bimodal mechanically interlocked rotaxane-based imaging agents, constructed via the cucurbit[6]uril CB[6]-mediated alkyne-azide 'click' reaction. Two synthetic routes involving four- or six-component reactions are developed to access asymmetric rotaxanes.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
July 2022
University of Zurich, Department of Chemistry, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
Mechanically interlocked molecules present opportunities to construct therapeutic drugs and diagnostic imaging agents but harnessing supramolecular chemistry to make biologically active probes in water is a challenge. Here, we describe a rotaxane-based approach to synthesise radiolabelled proteins and peptides for molecular imaging of cancer biomarkers in vivo. Host-guest chemistry using β-cyclodextrin- and cucurbit[6]uril-catalysed cooperative capture synthesis produced gallium-68 or zirconium-89 radiolabelled metallo[4]rotaxanes.
View Article and Find Full Text PDFACS Org Inorg Au
December 2021
Van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098XH Amsterdam, The Netherlands.
Despite the advances in the synthesis of mechanically interlocked molecules, a generally applicable approach to interlocked natural products, such as lasso peptides, is yet to be formulated. While amino acid sequences have been introduced into several rotaxanes, the key structural components have always been dictated by the method used for supramolecular preorganization. In this work, we report the use of an ester-functionalized, aromatic δ-amino acid as the central covalent templating unit in the synthesis of both a [2]catenane and a [2]rotaxane from the same multimacrocyclic intermediate.
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