Rapid Combinatorial Synthesis of Aminoglycoside Antibiotic Mimetics:  Use of a Polyethylene Glycol-Linked Amine and a Neamine-Derived Aldehyde in Multiple Component Condensation as a Strategy for the Discovery of New Inhibitors of the HIV RNA Rev Responsive Element

Park, William K.C.; Auer, Manfred; Jaksche, Herbert; Wong, Chi‐Huey

doi:10.1021/ja9612817

Cited by 181 publications

(93 citation statements)

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“…Similar findings were reported from screening of designed neomycin B analogs targeting the A site of eubacterial 16S rRNA [93]. The A site [94] and HIV-1 RRE [101] were used for binding studies of aminoglycoside mimetics obtained by conventional [94] and combinatorial [101] synthetic derivatization of the neamine core with amino acids [101] and various amines [94]. In an attempt to explore the RNA binding capacity of amino sugar compounds by simplifying the structure of the aminoglycosides, a chemical library was synthesized by adding amino acid and amine side chains to a 2-aminoglucopyranoside synthon [91].…”

Section: Rational Design and Combina-torial Synthesis Of Rna Binderssupporting

confidence: 81%

Rational Drug Design and High-Throughput Techniques for RNA Targets

Hermann

Westhof²

2000

CCHTS

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RNA molecules are the only known molecules which possess the double property of being depository of genetic information, like DNA, and of displaying catalytic activities, like protein enzymes. RNA molecules intervene in all steps of gene expression and in many other biological activities. Like proteins, RNAs achieve those biological functions by adopting intricate three-dimensional folds and architectures. Further, as in protein sequences, RNA sequences contain signatures specific for threedimensional motifs which participate in recognition and binding. In regulatory pathways, RNA molecules exist in equilibria between transient structures differentially stabilized by effectors such as proteins or cofactors. Therefore, RNA molecules display their potential as drug targets on different levels, namely in three-dimensional folds, in structural equilibria and in RNA-protein interfaces. Several examples will be described together with the already available techniques for combinatorial synthesis and high-throughput screening of potential drug and target RNA molecules.

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Section: Rational Design and Combina-torial Synthesis Of Rna Binderssupporting

confidence: 81%

Rational Drug Design and High-Throughput Techniques for RNA Targets

Hermann

Westhof²

2000

CCHTS

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“…The linking of different yardstick synthons creates molecules carrying ammonium groups at 8 A Ê distances. The large variety of possible diamino-substituted six-membered rings forms an ideal basis for the application of combinatorial chemistry in the synthesis of aminoglycoside effectors (Park et al, 1996;Wang & Tor, 1997c).…”

Section: Discussionmentioning

confidence: 99%

Aminoglycoside binding to the hammerhead ribozyme: a general model for the interaction of cationic antibiotics with RNA 1 1Edited by J. Karn

Hermann

Westhof

1998

Journal of Molecular Biology

181

166

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A variety of drugs inhibit biological key processes by binding to a speci®c RNA component. We focus here on the well-analysed hammerhead ribozyme RNA that is inhibited by aminoglycoside antibiotics, a process considered as a paradigm for studying drug/RNA interactions. With insight gained from molecular dynamics simulations of the ribozyme in the presence of Mg 2 identi®ed by crystallography and of aminoglycosides in solution, a general model for aminoglycoside binding to RNA is proposed. A striking structurally based complementarity between the charged ammonium groups of the aminoglycosides and the metal binding sites in the hammerhead was uncovered. Despite dynamical exibility of the aminoglycosides, several of the intramolecular distances between the charged ammonium groups of the drugs were found to be rather constant. Intramolecular ammonium distances of the aminoglycosides span ranges similar to the interionic distances between Mg 2 in the hammerhead. Successful docking of aminoglycosides to the hammerhead ribozyme could be achieved by positioning the ammonium groups at the sites occupied by Mg 2 . The covalently linked ammonium groups of the aminoglycosides are thus able to complement in space the negative electrostatic potential created by a three-dimensional RNA fold. Consequently, it is suggested that aminoglycoside-derived sugars could constitute a basic set of yardstick synthons ideal for rational and combinatorial synthesis of drugs targeted at biologically relevant RNA folds.

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“…26À28 Carboxylmethyl-dimannose was obtained by ozonolysis of the alkene, 29 followed by further oxidation with Jones reagent. 26 Global deprotection under Birch reduction 30 furnished the fully deprotected α-1,2-linked dimannose ( Figure 1B).…”

Section: Abstract: Polyanhydrides Nanoparticles Carbohydrates Dendmentioning

confidence: 99%

Mannose-Functionalized “Pathogen-like” Polyanhydride Nanoparticles Target C-Type Lectin Receptors on Dendritic Cells

et al. 2011

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Targeting pathogen recognition receptors on dendritic cells (DCs) offers the advantage of triggering specific signaling pathways to induce a tailored and robust immune response. In this work, we describe a novel approach to targeted antigen delivery by decorating the surface of polyanhydride nanoparticles with specific carbohydrates to provide "pathogen-like" properties that ensure nanoparticles engage C-type lectin receptors on DCs. The surface of polyanhydride nanoparticles was functionalized by covalent linkage of dimannose and lactose residues using an amine-carboxylic acid coupling reaction. Coculture of functionalized nanoparticles with bone marrow-derived DCs significantly increased cell surface expression of MHC II, the T cell costimulatory molecules CD86 and CD40, the C-type lectin receptor CIRE and the mannose receptor CD206 over the nonfunctionalized nanoparticles. Both nonfunctionalized and functionalized nanoparticles were efficiently internalized by DCs, indicating that internalization of functionalized nanoparticles was necessary but not sufficient to activate DCs. Blocking the mannose and CIRE receptors prior to the addition of functionalized nanoparticles to the culture inhibited the increased surface expression of MHC II, CD40 and CD86. Together, these data indicate that engagement of CIRE and the mannose receptor is a key mechanism by which functionalized nanoparticles activate DCs. These studies provide valuable insights into the rational design of targeted nanovaccine platforms to induce robust immune responses and improve vaccine efficacy. The use of vaccine adjuvants to activate the innate immune system is crucial to vaccine effectiveness. 1 Adjuvants can be used to enhance the efficacy of single dose vaccines and reduce the required antigen dose. The use of biodegradable polymer nanoparticles as vaccine delivery vehicles allows for effective delivery of payloads by parental or mucosal administration by protecting the antigen from harsh physiological conditions and enabling transport across biological barriers (e.g., mucus membranes). 2 Polyanhydride nanoparticles have shown excellent potential as vaccine carriers. 3À6 Encapsulation of protein antigens into polyanhydride particles stabilizes them and provides sustained azntigen release; 4,7 these particles also enhance the immune response by acting as an adjuvant. 3 Dendritic cells (DCs) are antigen presenting cells (APCs) that play a major role in connecting the innate and adaptive immune systems, a key step to inducing protective immunity. 8 DCs can sense and internalize antigen by a variety of mechanisms that trigger DC maturation and direct further interactions with other immune cells, including naive T cells. 1,9,10 Pattern recognition receptors (PRRs) on DCs detect the presence of a potential threat by interacting with pathogen-associated molecular patterns (PAMPs). 10,11 In particular, C-type lectin receptors (CLRs) are PRRs with highly conserved carbohydrate-recognition domains that bind sugar moieties (e.g., mannose, fuco...

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Rapid Combinatorial Synthesis of Aminoglycoside Antibiotic Mimetics: Use of a Polyethylene Glycol-Linked Amine and a Neamine-Derived Aldehyde in Multiple Component Condensation as a Strategy for the Discovery of New Inhibitors of the HIV RNA Rev Responsive Element

Cited by 181 publications

References 20 publications

Rational Drug Design and High-Throughput Techniques for RNA Targets

Rational Drug Design and High-Throughput Techniques for RNA Targets

Aminoglycoside binding to the hammerhead ribozyme: a general model for the interaction of cationic antibiotics with RNA 1 1Edited by J. Karn

Mannose-Functionalized “Pathogen-like” Polyanhydride Nanoparticles Target C-Type Lectin Receptors on Dendritic Cells

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