Isis Pharmaceuticals, Inc.

Genelabs Technologies, Inc.

Biota Scientific Management Pty Ltd

Biota, Inc.

Thomas W Bruice

Phillip Dan Cook

David J Ecker

Timothy A Vickers

Charles John Guinosso

Walter F Lima

Kevin P Anderson

Ronnie C Hanecak

Guangyi Wang

Andrew Mamoru Kawasaki

Yi Jin

Marija Prhavc

Janet M Leeds

Jennifer L Brooks

Vivek K Rajwanshi

Nicholas A Boyle

Maria Eugenia Ariza

Patrick C Fagan

Kathleen D Tucker

Muthiah Manoharan

Richard Holmes Griffey

Jacqueline R Wyatt

Chikateru Nozaki

Albert W Tam

Fukusaburo Hamada

Gary P Schroth

Peter W Davis

Hiroshi Nakatake

Tsukasa Nishihara

Tatsuo Eto

Megan E Laurance

Kazuya Hoshiko

Shinichi Furukawa

Young J Suh

Douglas B Starr

Susan M Freier

Kirk E Fry

Yogesh S Sanghvi

Shoji Furusako

Jungsuh P Kim

Cynthia A Edwards

Vickie L Brown-Driver

Mark Douglas Velligan

Emil F Michelotti

Yan Kwok

Derek R Latour

Rita L Thomas

Ana Kongpachith

Liana T Sheppard

Moon Young Kim

Shoji Furasako

Moon Young Lim

The present invention relates to nucleoside diphosphate mimics and nucleoside triphosphate mimics, which contain diphosphate or triphosphate moiety mimics and optionally sugar-modifications and/or base-modifications. The nucleotide mimics of the present invention, in a form of a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutical formulation, are useful as antiviral, antimicrobial, and anticancer agents. The present invention provides a method for the treatment of viral infections, microbial infections, and proliferative disorders. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention optionally in combination with other pharmaceutically active agents.

Nucleotide mimics and their prodrugs

The present invention provides molecular switch system methods and compositions for use in regulatable gene expression. The system includes a nucleic acid construct which has a DNA response sequence for a transcriptional regulatory protein operably linked to a promoter, a compound binding sequence in the vicinity of the DNA response sequence, a transgene under the control of the promoter; and a DNA binding compound. In some cases, the molecular switch system further includes a nucleic acid sequence encoding a transcriptional regulatory protein operably linked to a second promoter. The invention further provides a method for screening compounds for the ability to function in the molecular switch system and thereby regulate gene expression.

DNA binding compound-mediated molecular switch system

This invention provides nucleic acid sequences, vectors and host cells comprising regulatory regions associated with various promoters including a cyclin D1 promoter, a CD40L promoter, three HBV promoters (core, pre-S1 and HBV-X), a vancomycin-resistant enterococci (VRE) promoter, an androgen receptor promoter, a Her2 promoter, and &#x3b2;-lactamase promoter. The invention further provides methods of regulating gene expression comprising the regulatory regions of such promoters.

Promoters for regulated gene expression

Compositions and methods for modulating the activity of RNA are disclosed. In accordance with preferred embodiments, antisense compositions are prepared comprising targeting and reactive portions. The reactive portions preferably comprise one or two imidazole functionalities conjugated to the targeting oligonucleotide via linkers with or without intervening intercalating moieties. Therapeutics, diagnostics and research methods also are disclosed, as are synthetic nucleosides and nucleoside fragments that can be elaborated into oligonucleotides.

Compositions and methods for modulating RNA

Antisense oligonucleotides are provided which are complementary to and hybridizable with at least a portion of HCV RNA and which are capable of inhibiting the function of the HCV RNA. These oligonucleotides can be administered to inhibit the activity of Hepatitis C virus in vivo or in vitro. These compounds can be used either prophylactically or therapeutically to reduce the severity of diseases associated with Hepatitis C virus, and for diagnosis and detection of HCV and HCV-associated diseases. Methods of using these compounds are also disclosed.

Compositions and methods for treatment of Hepatitis C virus-associated diseases

Methods for determining the relative binding affinities of various ligands to various nucleic acid sequences are described. In a direct binding assay, the effect of adding increasing amounts of a ligand on a signal generated by two &ldquo;indicator&rdquo; oligonucleotides is observed. Also described is a competitive binding assay, in which a competitor oligonucleotide is added to an indicator duplex having a ligand bound thereto. The assays allow the rapid and convenient determination of nucleic acid binding specificities and base pair determinants of specificity of particular ligands.

Nucleic acid ligand interaction assays

Methods for modulating expression of a gene are provided. The methods comprise the steps of selecting a portion of an RNA coded by the gene, wherein the RNA is capable of interacting with a protein, preparing an oligonucleotide or oligonucleotide analog to mimic the portion of the RNA, and contacting cells containing the gene with the oligonucleotide or oligonucleotide analog. Methods of treating a disease are also provided. The methods comprise selecting a portion of an RNA coded by a gene whose expression is believed to be responsible for the disease, preparing an oligonucleotide or oligonucleotide analog to mimic the portion, and contacting an organism suspected of having the disease with the oligonucleotide or oligonucleotide analog.

Reagents and methods for modulating gene expression through RNA mimicry

Compositions and methods for modulating the activity of RNA are disclosed, In accordance with preferred embodiments, antisense compositions are prepared targeting reactive portions. The reactive portions preferably comprise one or two imidazole functionalities conjugated to the targeting oligonucleotide via linkers with or without intervening intercalating moieties. Therapeutics, diagnostics and research methods also are disclosed, as are synthetic nucleosides and nucleoside fragments that can be elaborated into oligonucleotides.

Methods for determining the relative binding affinities of various ligands to various nucleic acid sequences, particularly in double stranded form, are described. In a direct binding assay, the effect of adding increasing amounts of a ligand on a signal generated by two &ldquo;indicator&rdquo; oligonucleotides is observed. Also described is a competitive binding assay, in which a competitor oligonucleotide is added to an indicator duplex having a ligand bound thereto. The assays allow the rapid and convenient determination of nucleic acid binding specificities and base pair determinants of specificity of particular ligands.

Oligonucleotides which selectively bind to target biomolecules are determined by in vitro assay of a pool of random oligonucleotides for activity against the biomolecules, followed by recovery and characterization of selected oligonucleotides. Oligonucleotides so determined may be utilized for therapeutic, diagnostic and research reagent purposes.

Determination of oligonucleotides for therapeutics, diagnostics and

Expression of genes may be modulated by employment of compositions which are capable of RNA mimicry. A portion of RNA coded by the gene whose expression is to be modulated is selected which is capable of interacting with one or more proteins. An oligonucleotide or oligonucleotide analog is then prepared in such a way as to mimic the portion of the RNA. Cells containing the gene are then contacted with the oligonucleotide or oligonucleotide analog to effect the modulation. Therapeutic compositions and methods, especially for the treatment of human immunodeficiency, are disclosed.

Methods for modulating the expression of viral genes are provided by selecting a portion of RNA coded by the gene, said RNA portion having subportions forming a secondary structure, and contacting the RNA with oligonucleotide of 6 to 50 which can bind with at least one of said subportions of the RNA. In accordance with the preferred embodiments, oligonucleotides are designed to bind to RNA secondary structures which are of significance to the expression of the gene coding for said RNA. In accordance with a preferred embodiment, methods of treatment of human immunodeficiency virus are similarly disclosed wherein the oligonucleotides are targeted at the CAR or gag-pol region of HIV RNA.

Modulation of gene expression through interference with RNA secondary

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Carlsbad, CA, United States of America

Thomas W Bruice