Self-assembly of bivalent protein-binding agents based on oligonucleotide-linked organic fragments

Sprinz, K. Ingrid; Tagore, Debarati M.; Hamilton, Andrew D.

doi:10.1016/j.bmcl.2005.05.094

Cited by 64 publications

(49 citation statements)

References 15 publications

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“…[18,22,23,25] Different ways to generate large repertoires of DNA-encoded compounds have been suggested in recent years, such as alternate parallel synthesis, [13] sequence-encoded routing, [26] DNA-templated organic synthesis [15] and encoded self-assembling chemical libraries. [19,27] We have recently described the construction of a DNA-encoded chemical library with 4 000 library members (termed DEL-4000), based on the stepwise addition of two chemical building blocks and the corresponding DNA sequences within the DNA fragment serving as coding tag (Figure 1 a). [18] In a typical selection experiment, the library is incubated with an immobilized target protein of choice, nonbinders are removed by stringent washing, and the enriched library compounds are amplified by polymerase chain reaction (PCR) and identified by high-throughput sequencing (Figure 1 b).…”

Section: Introductionmentioning

confidence: 99%

Isolation of a Small‐Molecule Inhibitor of the Antiapoptotic Protein Bcl‐xL from a DNA‐Encoded Chemical Library

et al. 2010

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Bcl-xL is an antiapoptotic member of the Bcl-2 protein family and an attractive target for the development of anticancer agents. Here we describe the isolation of binders to Bcl-xL from a DNA-encoded chemical library using affinity-capture selections and massively parallel high-throughput sequencing of >30,000 sequence tags of library members. The most potent binder identified, compound 19/93 [(R)-3-(amido indomethacin)-4-(naphthalen-1-yl)butanoic acid], bound to Bcl-xL with a dissociation constant (K(d)) of 930 nM and was able to compete with a Bak-derived BH3 peptide, an antagonist of Bcl-xL function.

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Section: Introductionmentioning

confidence: 99%

Isolation of a Small‐Molecule Inhibitor of the Antiapoptotic Protein Bcl‐xL from a DNA‐Encoded Chemical Library

et al. 2010

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“…[4] Such DNAencoded chemical libraries may be constructed as singlepharmacophore libraries (in which suitable chemical moieties are added in a stepwise fashion to molecular scaffolds [5][6][7][8] ) or as dual-pharmacophore chemical libraries (also termed encoded self-assembling chemical (ESAC) libraries [9,10] ). This second methodology is particularly suited for the improvement of binding affinity and specificity, starting from lead compounds of modest potency.…”

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confidence: 99%

Isolation of High‐Affinity Trypsin Inhibitors from a DNA‐Encoded Chemical Library

et al. 2007

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Maturing is easy to do: Annealing benzamidine–oligonucleotide conjugates with a library of DNA‐encoded compounds allows the affinity capture of pharmacophores that are capable of binding to exosites adjacent to the primary substrate‐binding pocket of the serine protease trypsin. Selected conjugates show an improvement in IC50 values of several orders of magnitude compared with the starting benzamidine.

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“…trivalent zu präsentieren. [141][142][143] Ein weiteres aktuelles Beispiel ist die Untersuchung bivalenter Wechselwirkungen im homodimeren Östrogenre-zeptor mit einem Rezeptorabstand von 3.9 nm (Abbildung 14). Abgesehen von der Kristallstruktur in Gegenwart verschiedener Liganden sind auch erste bivalente Liganden mit flexiblen Spacern bekannt.…”

Section: Pna/dnaunclassified

Multivalenz als chemisches Organisations‐ und Wirkprinzip

et al. 2012

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Multivalente Wechselwirkungen können universell zur gezielten Bindungsverstärkung zwischen verschiedenen Grenzflächen oder Molekülen genutzt werden. Die Bindungspartner bilden dabei kooperativ multiple Rezeptor‐Ligand‐Wechselwirkungen, die auf einzelnen schwachen, nichtkovalenten Bindungen basieren und daher prinzipiell reversibel sind. Daher spielen multi‐ und polyvalente Wechselwirkungen in biologischen Systemen eine entscheidende Rolle für Erkennungs‐, Adhäsions‐ und Signalprozesse. Die wissenschaftliche und praktische Etablierung dieses Prinzips wird anhand der Entwicklung von natürlichen Systemen über einfache artifizielle und theoretische Modelle hin zu anwendungsorientierten funktionalen Systemen demonstriert. Anhand eines systematischen Überblicks über Gerüstarchitekturen werden die zugrunde liegenden Wirk‐ und Steuerungsmöglichkeiten aufgezeigt und Designvorschläge für möglichst effektive multivalente Bindungspartner bis hin zu polyvalenten Therapeutika aufgezeigt.

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Self-assembly of bivalent protein-binding agents based on oligonucleotide-linked organic fragments

Cited by 64 publications

References 15 publications

Isolation of a Small‐Molecule Inhibitor of the Antiapoptotic Protein Bcl‐xL from a DNA‐Encoded Chemical Library

Isolation of a Small‐Molecule Inhibitor of the Antiapoptotic Protein Bcl‐xL from a DNA‐Encoded Chemical Library

Isolation of High‐Affinity Trypsin Inhibitors from a DNA‐Encoded Chemical Library

Multivalenz als chemisches Organisations‐ und Wirkprinzip

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