Complex synthetic chemical libraries indexed with molecular tags.

Ohlmeyer, Michael; Swanson, R. N.; Dillard, Lawrence W.; Reader, John; Asouline, G.; Kobayashi, Ryouji; Wigler, Michael; Still, W. Clark

doi:10.1073/pnas.90.23.10922

Cited by 470 publications

(232 citation statements)

References 11 publications

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“…the greatest utility. To construct such structurally diverse libraries while allowing the assignment of a structure to each member, we use a set of chemically stable molecular tags during solid-phase synthesis on polymeric beads (8). These tags can be used to unambiguously encode each bead with the synthetic scheme for its library member and are sufficiently robust to allow a wide range of chemical reactions during ligand construction.…”

mentioning

confidence: 99%

A paradigm for drug discovery employing encoded combinatorial libraries.

Burbaum¹,

Ohlmeyer²,

Reader³

et al. 1995

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

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confidence: 99%

A paradigm for drug discovery employing encoded combinatorial libraries.

Burbaum¹,

Ohlmeyer²,

Reader³

et al. 1995

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

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“…Photocleavable tags were synthesized as previously described by Still and colleagues (35). RNA phosphoramidite was purchased from Glen Research (Sterling, VA).…”

Section: Reagentsmentioning

confidence: 99%

Discovery of a Small Molecule Tat-trans-Activation-responsive RNA Antagonist That Potently Inhibits Human Immunodeficiency Virus-1 Replication

Hwang

Tamilarasu

Kibler

et al. 2003

Journal of Biological Chemistry

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Antiretroviral therapy to treat AIDS uses molecules that target the reverse transcriptase and protease enzymes of human immunodeficiency virus, type 1 (HIV-1).A major problem associated with these treatments, however, is the emergence of drug-resistant strains. Thus, there is a compelling need to find drugs against other viral targets. One such target is the interaction between Tat, an HIV-1 regulatory protein essential for viral replication, and trans-activation-responsive (TAR) RNA. Here we describe the design and synthesis of an encoded combinatorial library containing 39,304 unnatural small molecules. Using a rapid high through-put screening technology, we identified 59 compounds. Structure-activity relationship studies led to the synthesis of 19 compounds that bind TAR RNA with high affinities. In the presence of a representative Tat-TAR inhibitor (5 M TR87), we observed potent and sustained suppression of HIV replication in cultured cells over 24 days. The same concentration of this inhibitor did not exhibit any toxicity in cell cultures or in mice. TR87 was also shown to specifically disrupt Tat-TAR binding in vitro and inhibit Tat-mediated transcriptional activation in vitro and in vivo, providing a strong correlation between its activities and inhibition of HIV-1 replication. These results provide a structural scaffold for further development of new drugs, alone or in combination with other drugs, for treatment of HIV-1-infected individuals. Our results also suggest a general strategy for discovering pharmacophores targeting RNA structures that are essential in progression of other infectious, inflammatory, and genetic diseases.

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“…For example, peptide [27] or oligonucleotide [28] labels have been synthesized on the beads in parallel to the target molecules and then sequenced for bead decoding. Alternatively, haloarene tags have been incorporated during synthesis and then identified with high sensitivity using electron-capture gas chromatography detection [29]. In addition to the increased time and cost for the synthesis of a library containing tagging moieties, the tagging groups themselves might interfere with screening giving false positive or negative results.…”

Section: Mass Spectrometric Deconvolution Of Ratio-encoded Combinatormentioning

confidence: 99%

Analysis and screening of combinatorial libraries using mass spectrometry

Shin

Breemen

2001

Biopharm & Drug Disp

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Mass spectrometry is a highly selective and high throughput analytical technique that is ideally suited for the identification and purity determination of large numbers of compounds prepared using combinatorial chemistry or for the dereplication of natural products. Compounds may be characterized based on molecular weight, elemental composition and structural features based on fragmentation patterns. When coupled to a separation technique such as highperformance liquid chromatography (HPLC) or capillary electrophoresis, mass spectrometric applications may be expanded to include analysis of complex mixtures. However, the slower speed of the separation step reduces the throughput of the analysis. This review concerns the application of mass spectrometry to the characterization of combinatorial libraries and the screening of library and natural product mixtures. Strategies to enhance the throughput of LC-MS are discussed including fast HPLC and parallel LC-MS. Also, mass spectrometry-based screening methods are described including frontal affinity chromatography-mass spectrometry, gel permeation chromatography LC-MS, direct electrospray mass spectrometry of receptor-ligand complexes, affinity chromatography-mass spectrometry, and pulsed ultrafiltration mass spectrometry.

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Complex synthetic chemical libraries indexed with molecular tags.

Abstract: Combinatorial

Cited by 470 publications

References 11 publications

A paradigm for drug discovery employing encoded combinatorial libraries.

A paradigm for drug discovery employing encoded combinatorial libraries.

Discovery of a Small Molecule Tat-trans-Activation-responsive RNA Antagonist That Potently Inhibits Human Immunodeficiency Virus-1 Replication

Analysis and screening of combinatorial libraries using mass spectrometry

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