Amphiphilic cyclodextrins represent a new generation of these oligosaccharides, which are well known previously as host molecules in water. Cyclodextrins are now being modified with polar groups, lipophilic groups and conjugates which elaborate further their amphiphilicity and molecular recognition. The resulting amphiphiles are host molecules capable of forming all the assemblies expected of amphiphiles, but showing additional supramolecular properties. Examples of these macrocyclic amphiphiles are by now known that form thermotropic liquid crystals, while lyotropic assemblies include micelles, unimolecular micelles, nanoparticles, monolayers and bilayer vesicles. The assembly proper- Cyclodextrin Amphiphiles: A New Generation of CyclodextrinsCyclodextrins (CDs) are macrocyclic oligosaccharides composed of -(+)-glucopyranosyl units linked α(1Ǟ4).[a] Centre for Synthesis and Chemical Biology of the UCD Con-

Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using a computational strategy on a library of 46 656 heparan sulfate hexasaccharides we identified a rare sequence consisting of consecutive glucuronic acid 2‐O‐sulfate residues as selectively targeting HCII. This and four other unique hexasaccharides were chemically synthesized. The designed sequence was found to activate HCII ca. 250‐fold, while leaving aside antithrombin, a closely related serpin, essentially unactivated. This group of rare designed hexasaccharides will help understand HCII function. More importantly, our results show for the first time that rigorous use of computational techniques can lead to discovery of unique GAG sequences that can selectively target GAG‐binding protein(s), which may lead to chemical biology or drug discovery tools.

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A new series of amphiphilic cyclodextrins containing cationic groups at the 6-positions and alkyl or biolabile ester groups at the 2-positions has been synthesised. Selective 2-O-allylation followed by photochemical addition of lipophilic thiols made it possible to control lipophilicity in these mesomolecules and allow solubility and self-assembly in water. The cationic groups are cysteamine-derived, while the alkyl and ester groups are C(1)-C(16) and benzyl ester groups. This is a new general synthetic route to a potentially wide range of polycationic cyclodextrins capable of acting as gene delivery vectors by condensing DNA and forming liquid crystalline complexes with oligonucleotides.

Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), akey serpin present in human plasma, remain unknown. Using ac omputational strategy on alibrary of 46 656 heparan sulfate hexasaccharides we identified ar are sequence consisting of consecutive glucuronic acid 2-O-sulfate residues as selectively targeting HCII. This and four other unique hexasaccharides were chemically synthesized. The designed sequence was found to activate HCII ca. 250-fold, while leaving aside antithrombin, ac losely related serpin, essentially unactivated. This group of rare designed hexasaccharides will help understand HCII function. More importantly,our results show for the first time that rigorous use of computational techniques can lead to discovery of unique GAGsequences that can selectively target GAG-binding protein(s), which may lead to chemical biology or drug discovery tools.Heparin cofactor II (HCII) is as erine protease inhibitor (serpin) that circulates in human plasma at high levels. Although it has been known to selectively inhibit thrombin for several decades, [1][2][3] its true physiologic function remains to be understood. [4] HCII is known to bind to glycosaminoglycans (GAGs) such as dermatan sulfate (DS) and heparan sulfate (HS), which help mediate its inhibition of thrombin. One of the key reasons for the inability to identify HCIIs biologic role is the lack of knowledge on the specificity of HCII-GAGi nteraction.HCII is an interesting serpin. It bears considerable similarity to antithrombin (AT), another plasma serpin that mediates the anticoagulant action of heparin and fondaparinux, [5,6] two clinically used drugs.A Tand HCII are homologous in primary,secondary and tertiary structure ( Figure S1 in the Supporting Information). Yet, whereas AT binds specifically to fondaparinux sequence in heparin, [7] HCII is considered to bind non-specifically to heparin and HS. Further,a lthough both serpins display at wo-step,i nducedfit, allosteric activation mechanism in inhibiting their target enzymes, [8][9][10] no HS oligosaccharide has been discovered to induce robust activation of HCII.Identifying GAGs equences that selectively target proteins is extremely challenging.Akey reason for this is their structural complexity.H S, ah ighly anionic polymer containing variably sulfated, acetylated and epimerized residues, presents enormous structural diversity that makes comprehensive analysis of all possible sequences difficult. Thus, identifying key "needles" in this haystack, especially with synthesis [11,12] or isolation of oligosaccharides from nature nearly impossible. [13] We had earlier developed ad ual-filter computational algorithm, called combinatorial virtual library screening (CVLS) strategy,torapidly sort HS sequences into "specific" and "non-specific" bins. [14,15] We wondered whether this tool could pinpoint HS sequences that preferentially activate HCII for inhibition of thrombin. Further, we posited that such asequence,ifany,would be different from the pentasaccharide seq...

The ability of cyclodextrins to enhance the antiviral activity of a phosphodiester oligodeoxynucleotide has been investigated. A 18-mer oligodeoxynucleotide complementary to the initiation region of the mRNA coding for the spike protein and containing the intergenic consensus sequence of an enteric coronavirus has been tested for antiviral action against virus growth in human adenocarcinoma cells. The phosphodiester oligodeoxynucleotide only showed a limited effect on virus growth rate (from 12 to 34% viral inhibition in cells treated with 7.5 to 25 microM oligodeoxynucleotide, respectively, at a multiplicity of infection of 0.1 infectious particle per cell). In the same conditions, the phosphorothioate analogue exhibited stronger antiviral activity, the inhibition increased from 56 to 90%. The inhibitory effect of this analogue was antisense and sequence-specific. Northern blot analysis showed that the sequence-dependent mechanism of action appears to be the inhibition of mRNA transcription. We conclude that the coronavirus intergenic consensus sequence is a good target for an antisense oligonucleotide antiviral action. The properties of the phosphodiester oligonucleotide was improved after its complexation with cyclodextrins. The most important increase of the antiviral activity (90% inhibition) was obtained with only 7.5 microM oligonucleotide complexed to a cyclodextrin derivative, 6-deoxy-6-S-beta-D-galactopyranosyl-6-thio-cyclomalto-heptaose+ ++ in a molar ratio of 1:100. These studies suggest that the use of cyclodextrin derivatives as carrier for phosphodiester oligonucleotides delivery may be an effective method for increasing the therapeutic potential of these compounds in viral infections.

The synthesis of new 'bridged' p-cyclodextrin (p-CD) 'dimers' 7-12 was successfully achieved by two one-pot reactions from p-CD (3) and 6A-azido-6A-deoxy-p-CD (4). The 'phosphine imine' reaction was shown to be a superior approach compared to the Mitsunobu reaction as coupling strategy for the preparation of these 'dimers'. NMR Data, along with molecular-modelling calculations, suggest a 'helical-like' arrangement for the phenanthroline-diyl-linked 'dimer' derivative 9. Complexation properties of 9 were established by UV-VIS-spectrophotometric titration toward four metals. Among them Cu" or Eu"' ions were complexed selectively by 9, but no complexation occurred with La"' and Zn". In addition a specific and interesing esterase activity toward the phosphodiester bond of bis(4-nitrophenyl) phosphate anion was found in the case of the Cu" complex of 9.

New amphiphilic cyclodextrins fully substituted with sugar residues on the primary face have been synthesised and enzymatically modified.