Multivalency and Cooperativity in Supramolecular Chemistry

Badjić, Jovica D.; Nelson, Alshakim; Cantrill, Stuart; Turnbull, W. Bruce; Stoddart, J. Fraser

doi:10.1021/ar040223k

Cited by 624 publications

(399 citation statements)

References 60 publications

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“…Liposomes, polymers, dendrimers, nanoparticles, and even proteins and viruses have all been utilized for ligand presentation (Badjic et al, 2005;Kane, 2006;Kiessling et al, 2006;Lewis et al, 2006;Mammen et al, 1998). The engineering of novel polyvalent scaffolds remains an attractive area for future research.…”

Section: Choosing a Scaffoldmentioning

confidence: 99%

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Polyvalency: A promising strategy for drug design

Vance

Shah

Joshi

et al. 2008

Biotech & Bioengineering

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The simultaneous binding of multiple ligands on one entity to multiple receptors on another can result in an affinity that is significantly greater than that for the binding of a single ligand to a single receptor. This concept of ''polyvalency'' can be used to design molecules that are potent inhibitors of toxins and pathogens. We describe the design of potent polyvalent inhibitors that neutralize anthrax toxin in vivo as well as our attempts to elucidate the relationship between inhibitor structure and activity. We also highlight promising future avenues for research in polyvalent drug design.

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Section: Choosing a Scaffoldmentioning

confidence: 99%

“…In recent years, there has also been a tremendous interest in the design of novel polyvalent molecules (Badjic et al, 2005;Kane, 2006;Kiessling et al, 2006;Krishnamurthy et al, 2006;Mammen et al, 1998;Mulder et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Polyvalency: A promising strategy for drug design

Vance

Shah

Joshi

et al. 2008

Biotech & Bioengineering

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confidence: 99%

Stable and Potent Polyvalent Anthrax Toxin Inhibitors: Raft‐Inspired Domain Formation in Liposomes that Contain PEGylated Lipids

Rai¹,

Vance²,

Poon³

et al. 2008

Chemistry A European J

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The design of polyvalent molecules [1][2][3][4][5], consisting of multiple copies of a ligand attached to a suitable scaffold, represents a promising approach for designing potent inhibitors of pathogens and microbial toxins [1,[6][7][8][9][10][11]. Liposomes are particularly attractive scaffolds for designing polyvalent inhibitors [9,10,[12][13][14][15]; however, the poor colloidal stability of conventional liposomes and their short circulation times in vivo [16,17] are major obstacles limiting their therapeutic use. We describe the design of highly stable and active polyvalent anthrax toxin inhibitors based on liposomes incorporating polyethylene glycol (PEG)-functionalized lipids (PEGylated liposomes). Furthermore, drawing from the concept of lipid rafts [15,18,19] -domains that are believed to exist in cellular membranes -we have designed heterogeneous domain-containing PEGylated liposomes that are considerably more active than their homogeneous counterparts (Scheme 1). These raft-mimetic PEGylated polyvalent liposomes are attractive not only for designing inhibitors for toxins and pathogens, but also for the design of efficient targeted drug delivery systems.While liposomes have been investigated extensively for applications in drug delivery, as described above, conventional liposomes are limited in effectiveness because of their low colloidal stability and their rapid uptake by macrophage cells of the immune system, predominantly in the liver and spleen [20]. The ability to enhance the physical stability and extend the circulation lifetime through modification with PEG, achieved by using lipids with PEG attached to their hydrophilic head groups, has proven to be useful in the context of drug delivery [17,[20][21][22]. We first tested whether the use of PEGylated liposomes (Scheme 1b) would enable the design of stable and active polyvalent anthrax lethal toxin (LeTx) inhibitors.To that end, we made liposomes (100 nm diameter) composed of a 19:1 mixture of 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC) and a pyridyl dithiopropionate derivative of L-α-Distearoyl Phosphatidylethanolamine-N-[Amino(Polyethylene Glycol)2000] (DSPE-PEG2000-PDP). We functionalized these liposomes with an inhibitory peptide HTSTYWWLDGAPC [9,23] (4.7%) that binds to the heptameric cell-binding component of anthrax toxin, [PA 63 ] 7 , thereby blocking the binding of the toxic enzyme lethal factor (LF). Inhibition of the binding of LF to [PA 63 ] 7 prevents the cytosolic delivery of LF, thereby inhibiting cell death. Peptide-functionalized PEGylated liposomes protected RAW264.7 cells from LeTx with a half maximal inhibitory concentration (IC 50 ) of about 35 nM on a per-peptide basis; control PEGylated liposomes functionalized with thioglycerol showed no inhibitory activity (Fig. 1a). Furthermore, as seen in Fig. 1a, the activity of the polyvalent PEGylated liposomes (Scheme 1b) was comparable to that of conventional (non-PEGylated) DSPC-based liposomes (Scheme 1a) with the same peptide density (20 nM), indicating that the use of ...

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“…Lett. 2002, 4, 679-682) in a template-directed synthesis of a precursor bis [2]rotaxane that requires that a bisdibenzo [24]crown-8 core is threaded with a bis-(bromomethyl)-substituted dibenzylammonium ion derivative before stoppering is achieved with an excess of Ph 3P. The best yield obtained in this sequence of reactions was 37% overall, a major byproduct being the intermediate mono [2]rotaxane isolated in 28% yield.…”

Section: O M M U N I C a T I O N Smentioning

confidence: 99%

“…2002, 4, 679-682) in a template-directed synthesis of a precursor bis [2]rotaxane that requires that a bisdibenzo [24]crown-8 core is threaded with a bis-(bromomethyl)-substituted dibenzylammonium ion derivative before stoppering is achieved with an excess of Ph 3P. The best yield obtained in this sequence of reactions was 37% overall, a major byproduct being the intermediate mono [2]rotaxane isolated in 28% yield. Subsequent treatment of the bis [2]rotaxane with Fréchet-type wedge-shaped aldehydes (G1 and G2) effected Wittig reactions affording isomeric mixtures of tetraolefins, which were hydrogenated catalytically.…”

Section: O M M U N I C a T I O N Smentioning

confidence: 99%

Template-Directed Dynamic Synthesis of Mechanically Interlocked Dendrimers

et al. 2005

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Recently, the versatility of dynamic covalent chemistry (DCC) 1 has been demonstrated 2 in the multicomponent construction of complex mechanically interlocked compounds, such as molecular bundles 3 and nanoscale Borromean rings, 4 as well as in the highly efficient template-directed synthesis 5 of [2]rotaxanes. 6 Previously, we have reported 7 that, by employing DCC in the form of reversible imine bond formation, [2]rotaxanes with dialkylammonium ion (-CH 2 NH 2 + CH 2 -) recognition sites 8 encircled by [24]crown-8 macrocycles can be prepared in high yields by a thermodynamically controlled, templated self-assembly process, that is, a kind of clipping procedure (Figure 1), as a result of the mixing together of three different components, namely, a dialdehyde, a diamine, and a dumbbell compound containing a -CH 2 NH 2 + CH 2 -center to template the [2]rotaxane formation. 7 In the context of constructing mechanically interlocked dendrimers 9,10 by employing a convergent templation procedure, we have explored 11 the feasibility of using DCC to introduce dendrons onto multivalent cores carrying -CH 2 NH 2 + CH 2 -centers on their sidearms to act as "hooks" round which "eyes" in the shape of diimine-containing [24]crown-8 macrocycles can be constructed in an activating environment. We report herein that dendritic dialdehydes 1a-c from generation zero [G0] to generation two [G2], the diamine 2, and the trisammonium salt 3-H 3 ‚3PF 6 can be self-assembled (Scheme 1) as three collections of seven components, each in one-pot, under equilibrium conditions to afford the imine-containing [G0]-[G2] mechanically interlocked dendrimers 4a-c-H 3 ‚3PF 6 in yields in excess of 90%. These dynamic dendrimers can be converted into their kinetically stable, neutral amine-containing dendrimers 5a-c by reduction (fixation) of the imine bonds using the BH 3 ‚THF complex as the reducing agent, and then subsequently isolated as their fully protonated counterparts 5a-c-H 3 ‚3TFA after acidification with trifluoroacetic acid (H-TFA). 12 (see Supporting Information), the diamine 2 7 and the trisammonium salt 3-H 3 ‚3PF 6 1m were prepared according to procedures already described in the literature. The template-directed formation 5 of the [G0]-[G2] dendrimers requires only the mixing of 3 molar equiv of dendritic dialdehydes 1a-c with 3 molar equiv of the diamine 2 and 1 molar equiv of the dialkylammonium salt 3-H 3 ‚3PF 6 in either CD 3 CN or CD 3 NO 2 (concentration ∼35 mM) at room temperature. Such clipping experiments were monitored directly by 1 H NMR spectroscopy. By way of an example, Figure 2 shows (upper trace) the 1 H NMR spectrum (500 MHz, CD 3 NO 2 , 298 K) of the dynamic [G2]-dendrimer 4c-H 3 ‚3PF 6 recorded 5 min after mixing the three components in the requisite amounts (3:3:1 for 1:2:3-H 3 ‚3PF 6 ). The spectrum can be interpreted in terms of trace amounts of the starting materials plus the dynamic [G2]-dendrimer While the [G0]-[G2] dendritic dialdehydes 1a-c were obtained from their corresponding [G0]-[G2] dendritic brom...

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Multivalency and Cooperativity in Supramolecular Chemistry

Cited by 624 publications

References 60 publications

Polyvalency: A promising strategy for drug design

Polyvalency: A promising strategy for drug design

Stable and Potent Polyvalent Anthrax Toxin Inhibitors: Raft‐Inspired Domain Formation in Liposomes that Contain PEGylated Lipids

Template-Directed Dynamic Synthesis of Mechanically Interlocked Dendrimers

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