Methods for Selective Modifications of Cyclodextrins

Khan, Abdul Rauf; Forgó, Péter; Stine, Keith J.; D’Souza, Valerian T.

doi:10.1021/cr970012b

Cited by 807 publications

(1,102 citation statements)

References 247 publications

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“…This diameter is comparable to the PA 63 prepore internal diameter of 20-35 Å (11) and the diameter of the reconstituted pore, which is at least 11 Å at its most narrow part (25,26). Advanced methods exist for selective modification of cyclodextrins, and these offer established routes for synthesis of appropriate derivatives (27), for which many pharmaceutical applications have been described (28).…”

Section: Resultsmentioning

confidence: 99%

Blocking anthrax lethal toxin at the protective antigen channel by using structure-inspired drug design

Karginov

Nestorovich

Moayeri

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

111

160

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Bacillus anthracis secretes three polypeptides: protective antigen (PA), lethal factor (LF), and edema factor (EF), which interact at the surface of mammalian cells to form toxic complexes. LF and EF are enzymes that target substrates within the cytosol; PA provides a heptameric pore to facilitate LF and EF transport into the cytosol. Other than administration of antibiotics shortly after exposure, there is currently no approved effective treatment for inhalational anthrax. Here we demonstrate an approach to disabling the toxin: high-affinity blockage of the PA pore by a rationally designed low-molecular weight compound that prevents LF and EF entry into cells. Guided by the sevenfold symmetry and predominantly negative charge of the PA pore, we synthesized small cyclic molecules of sevenfold symmetry, ␤-cyclodextrins chemically modified to add seven positive charges. By channel reconstitution and high-resolution conductance recording, we show that per-6-(3-aminopropylthio)-␤-cyclodextrin interacts strongly with the PA pore lumen, blocking PA-induced transport at subnanomolar concentrations (in 0.1 M KCl). The compound protected RAW 264.7 mouse macrophages from cytotoxicity of anthrax lethal toxin ‫؍(‬ PA ؉ LF). More importantly, it completely protected the highly susceptible Fischer F344 rats from lethal toxin. We anticipate that this approach will serve as the basis for a structure-directed drug discovery program to find new and effective treatments for anthrax.infectious diseases ͉ membrane transport ͉ modified cyclodextrins

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Section: Resultsmentioning

confidence: 99%

Blocking anthrax lethal toxin at the protective antigen channel by using structure-inspired drug design

Karginov

Nestorovich

Moayeri

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

111

160

View full text Add to dashboard Cite

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“…Many CD derivatives have been synthesized as novel drug carriers to extend the physicochemical properties and inclusion capacity of natural CDs. 14,15 The CDs and modified CDs are often used as the promising excipients for the stability of drug during the fabrication of microspheres and nanoparticles (NPs). [16][17][18][19] In addition, high encapsulation efficiency (EE) could be achieved because of the inclusion ability of the CD moieties in the copolymers.…”

Section: Introductionmentioning

confidence: 99%

Hydroxypropyl-β-Cyclodextrin Copolymers and Their Nanoparticles as Doxorubicin Delivery System

Wang

Zhang

Liang

et al. 2011

Journal of Pharmaceutical Sciences

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“…Therefore, the outer and inner surface of the nanotube is covered with CDs. This result also indicates that the surface functionality of the nanotube can conveniently be controlled by the modification of the functionality of CD (30). For example, addition of per-6-thio-␥-CD into the vesicular solution of dendron 3 produced nanotubes with similar dimensions to those obtained with ␥-CD.…”

Section: Resultsmentioning

confidence: 63%

Cyclodextrin-covered organic nanotubes derived from self-assembly of dendrons and their supramolecular transformation

Park

Lee

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

133

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The dendritic building blocks with a focal pyrene unit self-organize into vesicles in aqueous phase. The in situ inclusion of the focal pyrene units into the cavity of ␤-or ␥-cyclodextrin (CD) induces self-assembled organic nanotubes with an average outer diameter of Ϸ45 nm and inner diameter of 22 nm. The surface of the nanotube is covered with CD. Therefore, the functional group on the surface of the nanotube is controlled simply by modifying the functionality of CD. The removal of CD from the nanotube with poly(propylene glycol) reversibly generates vesicles. This work provides an efficient methodology not only to create an additional class of CD-covered organic nanotubes but also to exhibit reversible transformation of nanotubes and vesicles triggered by the motifs of dendron self-assembly, CD inclusion, and pseudorotaxane formation.vesicle ͉ amphiphile S elf-assembly and transformation of biological or synthetic macromolecules in a wide range of scientific fields are crucial subjects for the achievement of well defined nanostructures and the precise control of the function of supramolecules at the molecular level (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). A multitude of biological or chemical assemblies including vesicle, tubule, fibril, and viral helical coats perform numerous biochemical operations in nature. In particular, vesicular and tubular assemblies are of much interest because of their unique characteristics as a biomimetic system, carrier for drug or gene, biochemical sensor, electronic or photonic material, nanoreactor, and template for hybrid structure (9-18). Therefore, in these viewpoints, self-assembly of synthetic building blocks by noncovalent interactions is expected to provide a unique methodology for creating supramolecular functional materials (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).Self-organization of dendrons (6) into supramolecular assemblies has been demonstrated in a thermotropic fashion (19,27), in aqueous phase (21-25), in organic media (20,22,23,26), and at solid-liquid interface (26). Recently, we reported that the amide dendrons can self-organize in various conditions to exhibit a multiplicity of architectures and functions (22-26). For the preparation of self-assembling nanomaterials, we designed the amide dendritic building blocks consisting of amide branches for hydrogen bonding, carboxyl functionality at the focal point, and alkyl tails for the stabilization of assembled structures by van der Waals interaction (22). Particularly, it was suggested that the dimeric form of the amide dendron, induced by secondary interactions such as hydrogen bonding and -interaction at the focal functional units, is the primary building block in the self-aggregation process in organic media (22,23,26). In addition, the amphiphilic nature of these amide dendritic building blocks provides an opportunity for the formation of various self-assembled nanostructures in aqueous phase. For example, we reported that the transition of the self-organiz...

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Methods for Selective Modifications of Cyclodextrins

Cited by 807 publications

References 247 publications

Blocking anthrax lethal toxin at the protective antigen channel by using structure-inspired drug design

Blocking anthrax lethal toxin at the protective antigen channel by using structure-inspired drug design

Hydroxypropyl-β-Cyclodextrin Copolymers and Their Nanoparticles as Doxorubicin Delivery System

Cyclodextrin-covered organic nanotubes derived from self-assembly of dendrons and their supramolecular transformation

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