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Assay for Integration Inhibitors Using Pre-Integration Complexes (S97022B.pdf)

Inventors
Frederic Bushman, Tal Kafri, Mark Hansen

Applications
Infection, HIV, Drug Discovery
A screen for viral integrase inhibitors

The invention describes an assay for viral integration inhibitors using pre-integration complexes (PICs). A cell line expressing high titers of HIV-based vectors has been developed. The vector particles produced have been used to generate PICs containing HIV integrase and other HIV proteins. This technique provides a source of PICs that are much safer to handle than live virus derived from Molt IIIB. Integrase is one of three enzymes encoded by HIV. Inhibitors of reverse transcriptase and protease have been shown to be effective in treatment of HIV infection. Similarly integrase is a promising, non-toxic target for drug therapy since there are no similar proteins known to be important for normal cell function. Despite extensive efforts, no clinically useful integrase inhibitors have been developed. In this invention, vector-based PICs were used to devise a microtiter plate-based assay for integration directed by PICs. The response to inhibitors by PICs is more authentic than purified recombinant integrase making them attractive for use in screens for inhibitors. Purified integrase protein can be inhibited by diverse compounds, complicating the identification of promising leads. However, assays with PICs are more resistant to inhibition and display a response that more closely matches the response of virus in vivo. Microtiter assay results can be obtained by PCR and gel analysis or use of the TaqMan gene quantification method..

References
Nat Biotechnol 17(6):578-82 (June 1999)

Patent Status:

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Method of Rapidly Identifying Inhibitors of Topoisomerase DNA Religation (S00014.pdf)

Inventors
Frederic Bushman and Young Hwang

Applications
Infection, Oncology, Antibacterials, Antifungal, Antiviral, Drug Discovery and Development
High throughput screen for compounds that modulate topoisomerase activity

Topoisomerases play a central role in nucleic acid metabolism and are important in a variety of biological processes related to cell division, DNA replication, chromosome structure and gene expression. Compounds that act as effective cellular inhibitors of topoisomerases are expected to act as cytotoxic agents through the disruption of the normal cell division process. Such compounds can be effective and selective antibacterial, antifungal and antiviral agents. And because cell division is an important characteristic of cancers and other proliferative diseases, agents that inhibit topoisomerases are also useful as antineoplastic agents. The invention provides methods for identifying topoisomerase activity modulators in both solid and liquid phase formats. High throughput screening methods, compositions, kits and integrated systems for performing the assays are provided. The invention represents an improvement over existing technology in several ways. Through the use of different nucleic acid substrates, the assays can be adapted to screen for inhibitors of numerous different classes of topoisomerase enzymes and assay multiple different topoisomerase enzymes in a single reaction, thus enhancing throughput. The assays can be run in a parallel fashion such that multiple different topoisomerase enzymes and/or modulators are assayed simultaneously. The assays can be performed in the liquid or solid phase and each of the formats is readily amenable for automation and high throughput screening. Further, the assays are are extremely sensitive relative to previous assay formats and only minimal quantities of reagents are required..

References
Nucleic Acids Res 28(24):4884-92 (December 2000)

Patent Status:

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Compositions and Methods for Producing Recombinant Membrane-Associated Proteins (S04009B.pdf)

Inventors
Tarmo Roosild, Jason Greenwald, Senyon Choe, Roland Riek, Mark Vega

Applications
Research Tool, Drug Discovery and Development, Membrane Protein Production
A 'partner' molecule called Mistic makes widespread production of large quantities of membrane proteins possible for the first time, allowing scientists to determine their atomic structure and design drugs that interfere with disease processes involving crucial proteins such as ion channels and GPCRs.

Membrane proteins are crucially important in medical research and drug discovery, but until now human membrane proteins have been virtually impossible to produce in large enough amounts to study. Out of approximately 10,000 human genes dedicated to integral membrane proteins, such as receptors and ion channels, only a small handful of proteins have been made available from natural sources in the quality and quantity needed to study them successfully in isolation. The discovery of Mistic, which facilitates the integration of cloned membrane proteins into the E. coli cell membrane, gives medical researchers a new tool that could revolutionize membrane biology. Mistic is an unusual Bacillus subtilis integral membrane protein, with a structure that consists of a bundle of four helices that fold autonomously into place within the cell membrane, bypassing the cellular translocon machinery. This self-integrating, or auto-inserting, ability of Mistic facilitates the rest of the molecule, the "cargo" protein, to undergo the folding and integration process. Mistic allows scientists for the first time to produce large quantities of crucial membrane proteins for structural study or therapeutic research, such as ion channels and the vast family of receptors called G-protein coupled receptors (GPCRs). More than half the blockbuster drugs in the pharmaceutical industry target these two classes of proteins. Salk researchers have successfully created dozens of such important human membrane proteins in the cell membrane of E. coli using Mistic. _ In addition, experiments suggest that Mistic can be used for high-level production of other membrane proteins in their native conformations, including many eukaryotic proteins that have previously been intractable to recombinant bacterial expression.

References
Science 307:1317-8

Patent Status:
U.S. Patent Application Published as US-2006-0211087 A1

License Terms:
Exclusive or Non-Exclusive Licenses available by Field of Use

Reference_Number: S04009B
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu

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Method of Regulating Transcription in a Cell and Methods of Modulating Gene Expression (S00004.pdf)

Inventors
Beverly Emerson and Shilpa Kadam

Applications
Drug Discovery, Regulation of Gene Expression, Chromatin Remodeling
Chromatin based technology to define novel and highly specific protein targets for selective gene modulation

Appropriate differentiation and development of higher organisms require precisely regulated expression of multiple genes. The packaging of DNA into chromatin within the eukaryotic nucleus is highly organized and plays a critical role in regulating gene expression. The various types of chromatin structures that form on individual genes determine whether a gene is turned on or off. Regulation of chromatin structure is a critical component of gene regulation which affects tissue differentiation and cell function related to aging, cancer and a variety of diseases caused by changes in gene expression. Drug discovery related to modulation of gene expression, either to down regulate an overexpressed gene or to up regulate a silenced gene cannot be done at the DNA level alone. Chromatin based assays allow for the natural state of DNA regulation and provide optimal targets for therapeutic intervention. One important family of mammalian chromatin remodeling complexes, SWI/SNF (switch/sniff) is targeted to individual genes to specifically regulate its expression. SWI/SNF interacts with only certain classes of transcription factors and this property enables SWI/SNF to be selectively recruited to particular promoters. For example, proteins containing zinc finger DNA-binding domains (ZF DBDs), which is the largest class of eukaryotic transcription factors, interact with the BRG1 subunit of human SWI/SNF complex and recruit this complex to target promoters rather than the other catalytic subunit of SWI/SNF, BRM complexes. One invention provides for screening assays that identify small molecules that enhance or block the association between chromatin remodeling complexes and the specific transcription factors with which they interact. Specifically, the assays utilize several families of chromatin remodeling complexes which play key roles in facilitating the binding of specific transcription factors to nucleosomal DNA in diverse organisms from yeast to man. These in vitro assays can be developed for high-throughput screening to identify small molecule drugs that alleviate specific diseases caused by gene over or under expression. The second invention relates to three new findings of commercial potential. First, ZF DBDs or peptides are sufficient to direct SWI/SNF to a repressed promoter and create an accessible chromatin structure which enables other transcription factors to interact and activate the gene. In the absence of the ZF DBD, SWI/SNF and the other factors do not interact and the gene remains silent. Second, SWI/SNF BRG1 complexes, but not BRM, bind to the CREB transcription factor only when phosphorylated. CREB is the critical regulator of cAMP-response genes and thus a direct link between this signaling pathway and targeted chromosomal binding and gene activation by a specific form of SWI/SNF is established. Third, the opposite specificity exists for another type of signaling pathway. In this case, BRM SWI/SNF, but not BRG1, interacts with critical regulators of the Notch signaling pathway and is recruited to Notch target genes. Thus it is possible to identify drugs that selectively inhibit one type of pathway without affecting others..

References
S00004: Cell 95(1):93-104(October 1998)
S02019: Molecular Cell 11:377-389 (February 2003)

Patent Status:
U.S. Patent Application published as 2002-0022021
U.S. Patent Application published as 2005-0079512

License Terms:
Non-Exclusive Licenses Negotiable

Reference_Number: S00004
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu

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Compounds Useful for the Modulation of Processes Mediated by Nuclear Hormone Receptors, Methods for the Identification and Use of Such Compounds (S97012.pdf)

Inventors
Ronald Evans and Laszlo Nagy

Applications
Oncology, Drug Discovery and Development
Compositions for treatment of cancer, comprised of a ligand for a member of the steroid/thyroid hormone superfamily of receptors and a histone deacetylase inhibitor

It has been discovered that histone deacetylase associates with hormone receptor complexes and contributes to the repression thereof. It has further been discovered that exposure of a repressed system to histone deacetylase inhibitors relieves this repression. Thus, histone deacetylase inhibitors have been found to be useful for the activation of genes responsive to hormone receptors. The invention includes compositions for the treatment of cancer, which are made up of a ligand for a member of the steroid/thyroid hormone superfamily of receptors and a histone deacetylase inhibitor. Preferred ligands are ligands for retinoid receptors (e.g., all-trans retinoic acid, 9-cis retinoic acid), ligands for thyroid hormone receptors or ligands for vitamin D3 receptor. Preferred inhibitors included histone deacetylase inhibitors (e.g., Trichostatin A, Trapoxin), and chromatin remodeling machinery inhibitors..

References
Cell 1997 May 2;89(3):373-80
Nature 1998 Feb 19;391(6669):811-4
Published PCT application WO98/48825

Patent Status:

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Selective Modulators of PPAR-gamma and Methods for the Use Thereof (S95031.pdf)

Inventors
Ron Evans and Barry Forman

Applications
Cardiovascular, Obesity, Drug Discovery and Development
Use of PPAR-gamma-selective compounds for the treatment of obesity and diabetes.

Because obesity is associated with the development of serious medical conditions, including noninsulin-dependent diabetes mellitus, hypertension, coronary artery disease, hyperlipidemias and certain malignancies, it is important that compounds to control adiposity are identified. The conversion of fibroblasts into cells of the adipose lineage is induced by expression of the orphan nuclear receptor PPAR-gamma. Accordingly, an endogenous PPAR-gamma ligand may be an important regulator of adipogenesis. This invention reveals PPAR-gamma as a drug target and relates to a class of compounds which are capable of selectively modulating processes mediated by PPAR-gamma. The identification of such compounds makes possible the selective intervention in PPAR-gamma mediated pathways, without exerting inadvertent effects on pathways mediated by other PPAR isoforms..

References
Cell 1995 Dec 1;83(5):803-12.

Patent Status:
U.S. Patent No. 6,830,882 issued December 14, 2004

License Terms:
Exclusive or Nonexclusive licenses available

Reference_Number: S95031
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Treatment of Disease States which Result from Neoplastic Cell Proliferation Using PPAR-gamma Activators and Compositions Useful Therefor (S96024A.pdf)

Inventors
Ron Evans, Laszlo Nagy, and Peter Tontonoz

Applications
Oncology, Drug Discovery and Development
Administration of PPAR-gamma agonists, optionally in combination with RXR specific agonists, can block neoplastic cell proliferation

Neoplastic cell proliferation is the underlying cause of a wide variety of diseases, e.g., breast cancer, leukemia, colon cancer, prostate cancer. Traditional approaches to treatment of neoplastic cell proliferation include surgery, chemotherapy and radiotherapy. Induction of terminal differentiation represents a promising alternative to conventional methods of treatment for certain malignancies. It has been discovered that PPAR-gamma is expressed consistently in tissues associated with a variety of disease states which result from neoplastic cell proliferation. Maximal activation of PPAR-gamma with exogenous ligand promotes terminal differentiation of primary cells which are otherwise subject to neoplastic cell proliferation. Thus, cells undergoing neoplastic cell proliferation can be induced to differentiate, thereby blocking further proliferation. It has also been discovered that RXR-specific ligands are potent agents for induction of differentiation of cells expressing the PPAR-gamma/RXR-alpha heterodimer and that simultaneous treatment of cells subject to neoplastic cell proliferation with a PPAR-gamma-selective ligand, in combination with an RXR-specific ligand, results in an additive stimulation of differentiation. The invention includes compounds and compositions which could be useful for the treatment of breast cancer, leukemia, colon cancer and prostate cancer..

References
PNAS USA 1997 Jan 7; 94(1):237-41

Patent Status:

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Treatment of Liposarcomas Using a Combination of Thiazolidinediones and Retinoid X Receptor Selective Agonists (S96023A.pdf)

Inventors
Ron Evans, Peter Tontonoz, and Barry Forman

Applications
Oncology, Drug Discovery and Development
Compositions useful for the treatment of liposarcomas

Liposarcoma is the most common soft tissue malignancy in adults, accounting for at least 20% of all sarcomas in this age group. Localized disease is treated primarily with surgery, often in combination with radiotherapy. Metastatic liposarcoma is associated with an extremely poor prognosis, with average five year survival ranging from 70% to 25%, depending on the type of tumor. The development of effective, noninvasive methods for treating liposarcomas would represent a significant advancement in the therapeutic arts. It has been discovered that PPAR-gamma is expressed consistently in each of the major histologic types of human liposarcoma. Maximal activation of PPAR-gamma with exogenous ligand (a thiazolidinedione or derivative thereof) promotes terminal differentiation of primary human liposarcoma cells, thereby blocking further proliferation. It has also been discovered that RXR-specific ligands are potent adipogenic agents in cells expressing the PPAR-gamma/RXR-alpha heterodimer and that simultaneous treatment of liposarcoma cells with a thiazolidinedionyl moiety (a PPAR-gamma-selective class of compounds) and an RXR-specific ligand results in an additive stimulation of differentiation. The invention includes compositions useful for the treatment of liposarcomas..

References
PNAS USA 1997 Jan 7; 94(1):237-41

Patent Status:

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Use of RAR Antagonists as Modulators of Hormone Mediated Processes (S96028.pdf)

Inventors
Ron Evans, Laszlo Nagy, and Peter Tontonoz

Applications
Cardiovascular, Obesity. Drug Discovery and Development
RAR Antagonists are capable of modulating processes mediated by other members of the steroid/thyroid hormone receptor superfamily, including permissive receptors such as PPARs.

Retinoic acid receptor (RAR) antagonists are capable of modulating processes mediated by non-RAR members of the steroid/thyroid hormone receptor superfamily including permissive receptors such as PPARs (e.g., PPAR-alpha, PPAR-delta and PPAR-gamma). It has been discovered that RAR antagonists, in combination with agonists for members of the steroid/thyroid hormone receptor superfamily, are capable of inducing and/or enhancing processes mediated by such members. Such compositions will modulate the activity of permissive heterodimers. Permissive heterodimeric members of the steriod/thyroid hormone receptor superfamily include PPAR:RXR, LXR:RXR, NGFI-B:RXR, NURR1:RXR, FXR:RXR, BXR:RXR, SXR:RXR. For example, PPAR regulates genes involved in fatty acid degradation. This is blocked by retinoid agonists. In contrast, an RAR antagonist can stimulate PPAR signalling. Accordingly, a composition composed of an RAR antagonist and a PPAR agonist could represent a unique approach to treat PPAR controlled syndromes such as cardiovascular disease, hyperlipidemia, obesity or insulin resistance which are characterized by altered levels of fatty acids or their metabolites..

References
No publications to date

Patent Status:

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Orphan Receptor TLX and Uses Therefor (S04004.pdf)

Inventors
Yanhong Shi, Ruth Yu, Fred Gage, Ron Evans

Applications
Drug Discovery and Development, Adult Neural Stem Cells, Neurodegenerative Disease
Methods for identifying compounds that modulate the activity and expression of TLX: a nuclear receptor which maintains adult neural stem cells in an undifferentiated, proliferative state.

Neural stem cells are the self-renewing, multipotent cells that generate neurons, astrocytes, and oligodendrocytes in the nervous system. TLX was initially identified as an orphan nuclear receptor expressed in vertebrate forebrains and is highly expressed in the adult brain. In contrast, TLX -/- cells isolated from adult mutant brains fail to proliferate and self-renew. Reintroduction of TLX into the FACS-sorted TLX -/- cells rescues the ability to proliferate and self-renew. In vivo, the TLX mutant mice display a loss of cell proliferation and a significant reduction in nestin labeling in the adult neurogenic areas. Finally, TLX has been found to be capable of silencing glia-specific GFAP expression in neural stem cells, suggesting that transcriptional repression may be crucial in maintaining their undifferentiated state. This invention provides methods for identifying compounds which modulate the activity of TLX. Such compounds will find use in a wide variety of applications, e.g., methods for relieving TLX-mediated transcription repression and/or inducing processes mediated by TLX, methods for inhibiting processes mediated by TLX, and methods for promoting stem cell differentiation. The invention also provides methods for identifying compounds which modulate the expression of TLX. Such compounds will find use in a variety of applications, e.g., methods for treating neurodegenerative diseases (for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, retinal degeneration, age-related hearing loss, mild cognitive impairment, dementia, type II diabetes, myeloma); methods for reversing age-related depopulation of neural stems cells; methods for rescuing degenerated neural cell populations; methods for promoting generation of neural cell populations; methods for maintaining adult neural stem cells in an undifferentiated, proliferative state; and methods for rescuing or promoting neural stem cell activity..

References
Nature 427 (6969):78-83 (January 2004)

Patent Status:
U.S. Application Published as 2006-0040321

License Terms:
Exclusive, Partially Exclusive, Nonexclusive license negotiable

Reference_Number: S04004
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Transcription Factor Regulating FGF-2 and Variants Thereof (S98015.pdf)

Inventors
Fred H. Gage and Tetsuya Ueba

Applications
Oncology, Diagnostic, Drug Discovery
Genes which encode polypeptides that are FGF-2 regulators of transcription

This invention is based on the discovery of genes which encode polypeptides that are FGF-2 regulators of transcription (RFT). RFT-A, a negative regulator of transcription and RFT-A' and RFT-B, positive regulators of FGF-2 transcription are provided. The invention also relates to methods for diagnosis of prognosis for a subject having or at risk of having a disorder associated with FGF-2 and for treatment of cell proliferative disorders associated with FGF-2, such as neoplasia, atrocytoma, glioma, glioblastoma, medulloblastoma, colon cancer, lung cancer, renal cancer, leukemia, testicular cancer, breast cancer, prostate cancer, endometrial cancer and neuroblastoma. Screening methods for identifying a compound which affects RFT-A polypeptide or a variant of RFT-A polypeptide and for identifying proteins that bind to RFT-A polypeptide or a variant of RFT-A are also provided..

References
J Biol Chem 274(15): 10382-7 (April 1999)

Patent Status:

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IsK Knockout Mouse (ISK.pdf)

Inventors
Steve Heinemann

Applications
Molecular Neurobiology, CNS, Drug Discovery and Development
Mouse model for waltzer syndrome exhibiting hyperactivity, head tilt and bobbing

The IsK gene encodes a small protein of 129-130 amino acids that spans the cell membrane only once and gives rise to slowly activating, voltage dependent K+ conductances. The IsK gene is expressed in the kidney, heart and inner ear. Gene targeting techniques were used in mouse embryonic stem cells to produce mice with a null mutation of the IsK gene. A standard replacement vector was created and used to delete the entire coding sequence of the IsK gene. These IsK knockout mice, which express aberrant behavior due to the K+ channel defect, are models for the waltzer syndrome exhibiting hyperactivity, bi-directional circling, head tilt and bobbing..

References
Workshop on Inner Ear Biology, August 31 - September 3, 1996, Utrecht, The Netherlands
Nature 384: News and Views (1996)
J. Membr. Biol. 146: 283-291 (1995) and 147: 263-273 (1995)
Neuron 17: 1251-1264 (1996)

Patent Status:
No Application filed

License Terms:
Nonexclusive license negotiable

Reference_Number: ISK
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Kainate Receptor Subunit GluR7 Polymorphisms for Diagnosing Predisposition and for Therapy of Mood Disorders (S00007.pdf)

Inventors
Hans Schiffer and Stephen Heinemann

Applications
CNS, Mood Disorders, Diagnostic, Therapeutic, Drug Discovery
The Kainate Receptor Subunit GluR7 Gene is Associated with Mood Disorders

Mood disorders rank among the top ten causes of disability worldwide. Despite intensive research efforts, the specific genes involved in mood disorder pathology remain to be identified. Thus, it would be useful to identify the genes involved in mood disorders so as to improve diagnosis and therapy. The invention includes methods for determining the predisposition of a subject to a mood disorder by determining the presence of a kainate receptor subunit GluR7 allelic genotype or allelic phenotype. The invention also includes a method of treating or preventing a mood disorder and methods for identifying a compound useful for treatment. Transgenic non-human animals that express only a particular human GluR7 allele also are provided as a model of a human mood disorder..

References
The Journal of Neuroscience 20(24):9025-9033 (December 2000)

Patent Status:

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A Rapid Method to Determine Toxicity and Mutagenicity of Drugs and Chemicals (S05007.pdf)

Inventors
Merl F. Hoekstra

Applications
Drug Mutagenicity, Chemical Mutagenicity, DNA Strand Breakage and Repair
Compositions and Methods to Determine the Effects of Drugs and Chemicals on DNA Integrity.

Currently available lab tests to determine toxicity and mutagenicity of drugs and chemicals have limitations in extrapolating data from animals to humans. This results in uncertainties and inaccuracies in determining the effects of chemicals and drugs on DNA integrity. The invention provides a direct assay to determine if a chemical entity interferes with the DNA repair system of a cell. Recombinant HRR25-like protein products obtained according to the invention have been observed to display a number of properties which are unique among the eukaryotic protein kinases. HRR25 has both protein-tyrosine kinase and protein-serine/threonine kinase activities. HRR25 operates to promote repair of DNA strand breaks at a specific nucleotide sequence and is the only protein kinase known to have such recombination/repair promoting activity. The invention relates to a DNA encoding the HRR25 polypeptide which can be used in an assay system to examine the effects of various drugs and chemical compositions on DNA integrity. These sequences, which can be characterized by their ability to promote restoration of DNA strand breaks, permit the screening of chemical compositions to determine whether a particular chemical has an effect on the restoration of such repair activity. The invention also provides a DNA sequence encoding a polypeptide which promotes normal mitotic recombination, but is defective in protein kinase activity and essentially is unable to repair DNA strand breaks. This defective DNA sequence is highly useful for identifying other DNA sequences which encode proteins with functional protein kinase activity. Also, the invention defines the polypeptide encoded by the defective DNA sequence, as well as the polypeptide encoded by the functional wildtype DNA. .

References
Hoekstra, et al., Science 253 (5023): 1031-1034, 1991

Patent Status:
U.S. Patent No. 5,686,412 Issued November 11, 1997
U.S. Patent No. 5,756,289 Issued May 26, 1998

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Cyclin T, A New HIV Target (S97041.pdf)

Inventors
Katherine Jones, Ping Wei, Mitchell Garber, Shi-Min Fang

Applications
HIV, Drug Discovery and Development
Materials and methods useful for identifying compounds that prevent binding of Cyclin T to HIV Tat, thus disrupting HIV's infection cycle.

After HIV has settled into a chromosome, a viral protein called Tat (transactivating transcription factor) accelerates the production of new virus particles. Without Tat, an infection would not be likely to get off the ground. Researchers have known that Tat does not function alone, but requires help from a partner molecule in the cell. However, the nature of the cellular partner remained elusive. This invention covers the discovery of the molecule called cyclin T which appears to be Tat's partner. This discovery opens the door to developing a new class of therapeutic agents for AIDS based on blocking the chain of events created by the Tat-Cyclin T connection..

References
Genes & Development 11: 2593-2599 (1997)
Cell 92: 451-462 (1998)
Genes & Development 12: 3512-3527 (1998)
Mol. Cell. Biol. 20: 6958-6969 (2000)
J. Biol. Chem. 275: 34314-34319 (2000)

Patent Status:
U.S. Patent No. 6,284,456 issued September 4, 2001
Australian Patent No. 733100

License Terms:
Exclusive or Nonexclusive licenses available

Reference_Number: S97041
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Alpha-Complementation Viral Fusion Assay (S02016A.pdf)

Inventors
Carsten Muenk, Anne Holland and Nathaniel Landau

Applications
Antiviral Drug Discovery, Infection
A rapid and quantitative assay to detect HIV and other viral mediated fusion to screen for inhibitors

Entry is an attractive and promising step in HIV-1 replication to target with small molecules. Unlike current drugs that act mainly at reverse transcription or virus maturation, entry inhibitors protect cells from becoming infected and do not need to penetrate the cell. HIV-1 entry is mediated by the interaction of the viral glycoprotein with CD4 and either of the CC chemokine receptors, CCR5 or CXCR4. Current methods for high throughput screening for coreceptor antagonists have advantages and disadvantages. These assays include ligand-receptor competition assays, or cell based assays for cell-cell fusion, virus entry, or single cycle reporter virus infection. None of the assays directly measures the fusion event , but rather measure a secondary result of fusion. As a result, they pick up numerous false positives that act on irrelevant targets. The alpha complementation fusion assay described in the invention provides a means to directly detect envelope glycoprotein-mediated fusion. Moreover, the assay is much simpler and more rapid than any other method. Also, importantly, the assay does not use live virus and therefore can be performed without biohazard containment. The assay is done in 96 well microtiter plates and is easily adaptable to 384 or 1024 well format. The assay is scalable and easily adapted to high throughput screening. In addition, the assay can be adapted to any enveloped virus..

References
Virology 319(2):343-352 (February 2004)

Patent Status:
U.S. Patent Application Serial No. 10/729,069 filed December 4, 2003

License Terms:
Non-exclusive licenses available

Reference_Number: S02016A
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Sequence and Method for Increasing Protein Expression in Cellular Expression Systems (S99046.pdf)

Inventors
Martin Latterich and Kendall Powell

Applications
Infection, Protein Production, Antibiotics, Drug Discovery
A bacterial expression system to increase biomass and cellular protein production

There is a continuing need for improved cellular expression systems that produce higher yields of heterologous proteins and can be subjected to relatively easy production and purification techniques. The invention relates to a bacterial expression system which includes a novel protein, Vff2p (vesicular fusion factor 2), that, when expressed in a host cell, increases cellular biomass and cellular protein production and secretion. The invention also relates to a polynucleotide, VFF2, encoding the novel protein, methods for using the polynucleotide and encoded protein to increase cellular biomass and cellular protein production and secretion, methods of screening for antibiotics, as well as a genetically altered mutant cell strain with enhanced production and secretion of cellular and heterologous proteins..

References
No publications to date

Patent Status:

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Methods of Using Flavonoids to Enhance Memory (S06001.pdf)

Inventors
Pamela Maher

Applications
Drug Discovery and Development, Neutraceuticals.
A plant derived small molecule, the flavonoid Fisetin, shows efficacy as a neurotrophic factor promoting the differentiation of nerve cells, and has been shown to enhance long-term memory in mice. Polyphenolic compounds such as these may prove more effective than classical neurotrophic factors in treating neurological disorders.

Neurotrophic factors promote the differentiation, survival, and functional maintenance of nerve cells. Because of these properties, they have the potential to treat a variety of chronic and acute disorders of the central nervous system. Although there have been some successes, clinical use of classical neurotrophic factors, such as brain-derived neurotrophic factor, has been limited for technical reasons, including difficulty in crossing the blood-brain barrier. Therefore, the identification of small molecules that mimic some or all of the properties of neurotrophic factors could have significant potential for treating CNS disorders. A previous study by the inventor described the ability of the flavonoid Fisetin to promote the differentiation of nerve cells. Although a wide range of flavonoids were tested in that study, most failed to induce differentiation. Of the few effective flavonoids, Fisetin showed significantly greater efficacy than any of the others. The induction of differentiation by Fisetin depends on the activation of the Ras-extracellular signal-regulated kinase (ERK) cascade and in particular on the activation of the ultimate kinase in this cascade, ERK. Inhibitors of both Ras and ERK activation block Fisetin induced differentiation. Not only does Fisetin promote nerve cell differentiation, but in earlier studies it was shown to protect nerve cells from oxidative stress-induced death. Thus, Fisetin has several of the properties of classical neurotrophic factors. Experimental measurement shows that Fisetin facilitates LTP (Long Term Potentiation), the long-lasting strengthening of the connection between two nerve cells that is considered to be the cellular basis of learning and memory. Further experimentation with mice given Fisetin orally before training in an Object Discrimination Protocol indicates that Fisetin enhances long-term memory in mice. Fisetin could be useful for promoting memory in both normal subjects and in patients with neurological disorders, and its additional neurotrophic activities make Fisetin particularly attractive for promoting overall healthy brain function..

References
PNAS 103(44):16568-73 (31 October 2006)

Patent Status:
U.S. Application Filed July 19, 2006

License Terms:
Non-exclusive and Exclusive by Field of Use Licenses Negotiable

Reference_Number: S06001
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu

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Protein Kinase B/AKT Modulators and Methods of Use Thereof (S02011.pdf)

Inventors
Keyong Du, Stephen Herzig and Marc Montminy

Applications
Diabetes, Drug Discovery
A protein, TRB3, found to be overexrpessed in response to diabetes and fasting is an attractive drug target in the treatment of type II diabetes.

Under physiological conditions, binding of insulin to its receptor triggers the activation of a phospholipid-dependent kinase cascade that culminates in phosphorylation of the Ser-Thr kinase Akt also called PKB. The Akt family of kinases consists of three highly related family members: Akt1, Akt2 and Akt3. Among other essential pathways in glucose regulation, these critical kinases inhibit glycogenolysis, promote glycogen synthesis, and block gluconeogenic genes. These pathways are all involved in diabetes, and modulators of PKB/Akt kinases present novel methods of diagnosis and treatment. The invention describes modulators of PKB/Akt protein kinases that affect the phosphoylation state and activity of these enzymes. The modulators identified are TRB3 and related family members. TRB3 specifically inhibits Akt during fasting, and inappropriate expression of TRB3 in diabetes may contribute to insulin resistance by blocking Akt activity in the fed state. Thus TRB3 is an attractive drug target for the treatment of type II diabetes..

References
Science 300: 1574-1577 (June 6, 2003)

Patent Status:
U.S. Patent Application Filed June 12, 2003

License Terms:
Exclusive and Non-Exclusive Licenses Negotiable

Reference_Number: S02011
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu

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Modulation of Mevalonate-Independent Isoprenoid Biosynthetic Pathway (S00010B.pdf)

Inventors
Joseph Noel, Marianne Bowman and Stephane Richard

Applications
Infection, Drug Discovery, Natural Products, Agriculture, Plant Biology
Templates for the design of novel antibacterial and antiparasitic drugs

The invention provides the three dimensional structure of the enzyme 4-diphosphocytidyl-2-C-methylerythritol (CDP-ME) synthase, a member of the cytidyltransferase family of enzymes. CDP-ME is a critical intermediate in the mevalonate-independent pathway for isoprenoid biosynthesis in a number of prokaryotic organisms, in algae, in the plastids of plants and in the malaria parasite. Since vertebrates synthesize isoprenoid precursors using a mevalonate pathway, CDP-ME synthase and other enzymes of the mevalonate-independent pathway for isoprenoid production represent attractive targets for the structure-based design of selective antibacterial, herbicidal and antimalarial drugs. The invention provides methods for screening for compounds that inhibit enzymes of the mevalonate-independent pathway and pharmaceutical compositions and antibacterial formulations thereof. Further provided are methods of inhibiting the enzymes of the pathway and bacterial terpenoid synthesis and methods for treating a subject suffering from a bacterial infection..

References
Nat Struct Biol 2001 Jul: 8(7):641-8
Published PCT Application WO01/083769

Patent Status:
U.S. Application pending

License Terms:
Exclusive or Nonexclusive licenses available

Reference_Number: S00010B
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Novel Aromatic Prenyltransferases, Nucleic Acids Encoding Same and Uses Therefor (S04008B.pdf)

Inventors
Joseph P. Noel, Stephane Richard, Tomohisa Kuzuyama

Applications
Drug Discovery and Development
Enzyme that transfers a prenyl group is found to be unexpectedly promiscuous

A bacterial enzyme that transfers a prenyl group to an aromatic natural product may provide a general biosynthetic route to regioselective prenylation of aromatic small molecules. Many bioactive natural products contain isoprenoid chains of various lengths, collectively known as prenyl groups. New research has revealed biochemical and structural characterization of Orf2, a prenyltransferase enzyme that attaches a 10-carbon prenyl group to a polyketide during the biosynthesis of the antioxidant naphterpin. This enzyme has a novel barrellike architecture and is unexpectedly promiscuous. In vitro, Orf2 can regiospecifically prenylate a diverse collection of hydroxyl-containing aromatic molecules of microbial, plant, and synthetic origin. New information on the factors that control which prenyl chain is used and where it's appended on the substrate should guide the design of modified enzymes that can be used to alter the activity of natural products in bacteria, fungi, plants, and animals. This makes it possible to make rare prenylated natural products; and to carry out regioselective prenylation of aromatic chemicals..

References
Nature 2005 (435), 983.

Patent Status:
U.S. Application Published

License Terms:
Non-exclusive and Exclusive by Field of Use Licenses Negotiable

Reference_Number: S04008B
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Corticotropin-Releasing Factor (CRF) Antagonists (S96032.pdf)

Inventors
Jean Rivier and Wylie Vale

Applications
CNS, GI, Drug Discovery and Development
Drugs to activate CRF receptors based on peptide antagonists

The inventions relate to antagonists of the CRF hentetracontapeptides, as well as to members of the larger family of CRF-like peptides, to pharmaceutical compositions containing such CRF antagonists, and to methods of treating mammals using such CRF antagonists. CRF antagonists may be used to treat anxiety, depression, irritable bowel syndrome, immune suppression, Alzheimer's disease, hemorrhagic stress, drug addiction and withdrawal symptoms, and fertility problems. In addition, such CRF antagonists can provide the basis for valuable methods for drug screening in order to detect even more potent molecules that will bind to and/or activate CRF receptors..

References
Brain Research 744:166-170 (1997)
J. Med. Chem. 41: 5002-5011 (1998)
J. Med. Chem. 41: 5012-5019 (1998)
J. Med. Chem. 42: 2175-3182 (1999)
J. Pharm. Exp. Ther. 290(2): 629-634 (1999)

Patent Status:
U.S. Patent No. 5,109,111 issued 4/28/92
U.S. Patent No. 5,510,458 issued 4/23/96
U.S. Patent No. 5,874,227 issued 2/23/99

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Gonadotrophin Releasing Hormone (GnRH) Analogs (S96027.pdf)

Inventors
Jean Rivier, John Porter, Steven Koerber, Carl Hoeger

Applications
Drug Development, Oncology, Fertility
Potent GnRH antagonists with significantly increased duration of action, useful for applications including fertility regulation, endometriosis, hormone-dependent tumors, and precocious puberty.

GnRH is a hypothalamic decapeptide that stimulates the secretion of the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones modulate the levels of testosterone and estrogen in the body. The amino acid sequence of GnRH was discovered in 1971, and spawned the development of GnRH agonists and antagonists with many scientific and pharmaceutical perspectives. Certain advantages of antagonists are that they require a shorter administration period and pituitary suppression is immediately reversible after withdrawal of the antagonist. A breakthrough made at the Salk Institute was the discovery that acylated 4-aminophenylalanines in the L- and D-configurations at positions 5 and 6 respectively and an isopropyl-lysine at position 8 along with other established modifications at positions 1, 2, 3 and 10 yielded potent GnRH analogs with significantly increased duration of action. These antagonists are useful as fertility regulators (in vitro fertilization) and for the treatment of pathological conditions such as precocious puberty, hirsutism, acne, hormone dependent neoplasia, uterine myoma, amenorrhea, dysmenorrhea, endometriosis, PMS, ovarian and mammary cystic diseases, such as PCO, and hormone-dependent tumors, including malignant and benign prostatic, mammary, ovarian and testicular tumors..

References
J. Med. Chem. 1995, 38, 2649-2662
J Med Chem. 2000, 43(5):807-18

Patent Status:
U.S. Patent 5,352,796 issued Oct. 4, 1994 entitled Amino Acids Useful in Making GnRH Analogs
U.S. Patent 5,744,450 issued April 28, 1998 entitled GnRH Analogs

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Melanin-Concentrating Hormones (S48600.pdf)

Inventors
Joan Vaughan, Wolfgang Fischer, Jean Rivier, Jean-Louis Nahon, Francoise Presse, Wylie Vale

Applications
CNS, Oncology, Drug Discovery and Development
MCH as a therapeutic for suppression of melanoma-proliferation by topical application of melanin-concentrating hormones, or as a target for molecules acting on MCH

The invention relates to mammalian melanin-concentrating hormone (MCH), MCH precursors (NEI and NGE) and DNA encoding same. Mammalian MCH is useful to treat humans and other mammals to lighten skin color, by local or topical application. It is also useful to suppress the proliferation of certain skin tumor cells, such as melanomas, when suitably applied by topical application or the like. It is also found that mammalian MCH can be used to modulate the secretion of ACTH in humans and other mammals and thus can be used to modify the effects of stress, by systemically administering an effective amount of mammalian MCH..

References
Endocrinology 125: 1660-1665 (1989) and 130: 1024-1029 (1992)
Neuroscience Lett. 136: 145-149 (1992)

Patent Status:
U.S. Patent No. 5,449,766 issued September 12, 1995 (S55511)

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Methods of Inhibiting Poxvirus Growth (S05006.pdf)

Inventors
Bart Sefton, Roberta Schulte

Applications
Infection, Drug Discovery and Development, Poxvirus treatments
Targets for the development of anti-smallpox drugs

A drug that blocked poxvirus growth would be valuable if smallpox virus were to be used as a weapon. We have tested the ability of inhibitors of poxvirus protein kinases to inhibit poxvirus growth. Poxviruses encode two essential protein kinases, B1 and F10. We identified a number of small molecules that inhibited these protein kinases in vitro. One of these compounds inhibited the growth of vaccinia virus strongly. The drug reduced virus growth by 99% at a concentration of approximately 35 µM. This effect is apparently specific. This compound had no effect on the growth of the unrelated vesicular stomatitis virus or on the growth of human cells at a concentration that inhibited vaccinia growth by more than 90%. This compound shows promise for further development into an effective anti-small pox drug. In addition, the two essential viral protein kinases represent useful targets for the development of additional anti-poxvirus drugs..

References
No publications to date

Patent Status:
U.S. Patent Application filed October 10, 2005

License Terms:
Exclusive or Non-Exclusive Licenses Available

Reference_Number: S05006
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu

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Kir Channel Modulators (S06017.pdf)

Inventors
Scott Pegan, Paul Slesinger, Senyon Choe, Prafulla Aryal

Applications
Cardiology, CNS, Screening, Drug Discovery
Methods and materials for modulating Kir channel activity and identification of related compounds.

Inwardly-rectifying potassium (Kir) channel proteins are involved in a diverse range of biological processes, including regulation of cardiac and neurological functions. In contrast to voltage-gated potassium channels that allow large fluxes of K+ ions out of the cell when opened during membrane electrical activity, Kir channels allow fluxes of K+ ions out of the cell at resting membrane potentials, maintaining excitability. In addition, Kir channels are modulated by alcohols. Aberrant activity of Kir channels has been linked to a variety of endocrine, cardiac, and neurological disorders. In particular, mutations in Kir channel proteins have been implicated in analgesia, cardiac arrhythmias and Andersen's Syndrome. Consequently, new compounds discovered using the methods described could be therapeutically useful to control heart dysfunctions and neurological disorders such as epilepsy, as well as for developing novel analgesics. Scientists at the Salk Institute have recently determined the structure of the cytoplasmic domain of the Kir2 channel protein, and discovered that a small alcohol-like molecule, known as MPD, binds to a specific location within the protein domain. Additional studies indicate that low concentrations of MPD activate the related Kir3 subfamily of channel proteins. The Kir channel three-dimensional structure has been used to design mutants for characterizing the pharmacological properties of the alcohol pocket. This discovery provides a stereochemical basis for the systematic design, synthesis, and screening of related alcohol-like compounds in order to identify those that modulate Kir channel activities. The technology disclosed in the pending patent includes the elucidated structure of a representative Kir channel protein in combination with an alcohol and methods for identifying agents that modulate Kir channel activity and predicting whether an agent is capable of binding to a Kir channel..

References
Biochemistry. 46: 5315-5322 (2007)

Patent Status:
U.S. Patent Application filed 6/20/2007

License Terms:
Exclusive and Non-Exclusive Licenses available

Reference_Number: S06017
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu

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Corticotropin Releasing Factor-Binding Protein (CRF-BP) (S54426.pdf)

Inventors
Wylie Vale, Ellen Potter, Dominic Behan, Wolfgang Fischer, Elizabeth Linton, and Philip Lowry

Applications
CNS, Cardiovascular, Oncology, Obesity, Drug Discovery and Development
Proteins capable of binding and modulating the biological effect of CRF

The invention relates to CRF-BPs which are capable of binding to and modulating the biological effect of CRF and which have therapeutic applications. These CRF-BPs can be administered therapeutically to bind to and inactivate CRF thereby reducing high ACTH levels in mammals caused by excess CRF and can be used to treat Cushing's Disease, and the like. These CRF-BPs are also useful in combating pituitary tumors that produce CRF. Moreover, they can be used to reduce pituitary ACTH secretion and hence reduce cortisol levels under any condition in which they are abnormally high, such as during chronic stress or in patients afflicted with anorexia nervosa or alcoholism. CRF-BP or fragments thereof and/or antibodies to the proteins may be employed in diagnostic assays to determine the levels of CRF, CRF-BP and the ratio of CRF/CRF-BP in a vascular fluid sample. The DNA or subsequence thereof can be used as probes for genetic material in certain assays. The anti-CRF-BP antibodies are also useful to purify the CRF-BP protein and to modulate the biological effect of the CRF-BPs proteins. CRF-BPs can also be employed to screen for inhibitors which may be used to treat obesity and Alzheimer's disease..

References
Nature 349:423-426 (January 1991)
Genomics 16:63-68 (1993)

Patent Status:
U.S. Patent No. 5,733,790 issued March 31, 1998
U.S. Patent No. 5,910,428 issued June 8, 1999
Numerous Foreigns

License Terms:
Exclusive, Partially Exclusive, Nonexclusive license negotiable

Reference_Number: S54426
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Corticotropin-Releasing Factor Overproducing Transgenic Mice (S93011.pdf)

Inventors
Wylie Vale, Mary Stenzel-Poore, George Koob, Stephen Heinrichs

Applications
CNS, Drug Discovery and Development
Transgenic mouse useful to screen compounds that modulate corticotropin-releasing factor levels

This invention relates to a transgenic mouse model exhibiting chronic CRF hypersecretion. These animals express high levels of ACTH and corticosterone throughout their life span and develop phenotypic changes consistent with Cushing's disease and anxiety due to excess glucocorticoid production. Consequently, the invention transgenic mice are useful for a variety of applications, e.g., to screen for compounds that can modulate in-vivo CRF levels, and the like..

References
Endocrinology 130: 3378-3386 (1992)
J. Neuroscience 14: 2579-2584 (1993)

Patent Status:
U.S. Patent No. 6,166,287 issued December 20, 2000

License Terms:
Nonexclusive license negotiable

Reference_Number: S93011
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Compositions and Methods for Targeting a Polypeptide to the Central Nervous System (S03007.pdf)

Inventors
Inder Verma and Brian Spencer

Applications
Gene Therapy, Drug Development
Identification of modular targeting molecules that can selectively penetrate the blood-brain barrier

There exists a need for a mode or method that allows the passage of a specific therapeutic polypeptide across the blood-brain barrier. This invention is directed to the identification of modular targeting molecules that can selectively penetrate the blood-brain barrier (BBB). These chimeric CNS targeting polypeptides are comprised of a BBB binding domain and a payload polypeptide domain. The targeting molecules can carry and deliver any polypeptide of interest to the central nervous system (CNS). Such CNS targeting polypeptides have the advantage in that they can be administered directly to an individual, or they can be expressed via an encoding nucleic acid by non-target cells, and they will travel to and concentrate in the CNS. This approach will be applicable to lysosomal storage diseases such as Gaucher's disease, Hunter's disease and Fabry Syndrome. In addition the fusion of ligands to facilitate passage of proteins across the blood-brain barrier may be a general method for delivering therapeutic proteins to the CNS for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease or prion diseases..

References
Published PCT Application WO04/108071

Patent Status:
U.S. Application filed June 5, 2003

License Terms:
Exclusive, Partially Exclusive, Nonexclusive license negotiable

Reference_Number: S03007
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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A Novel Antitoxin and Vaccine Platform Based on Nodavirus VLPS (S07001.pdf)

Inventors
John Young, Anette Schneemann, Marianne Manchester, Kelly Dryden, John Harlett, Darly Manayani, Godfrey Rainey, Vilay Reddy, Marc Saladi, Heather Scobie, Diane Thomas, Mark Yeager

Applications
Infection, Vaccine, Drug Discovery and Development
A novel, chimeric virus-like particle (VLP) capable of multivalent display of PA shows significant advantages over existing monovalent PA immunogens for anthrax toxin. Studies indicate VLP-PA complex may eliminate the need for lengthy immunization schedules by providing immunity after a single injection, and has potential to generate effective vaccines against other pathogens, including combination vaccines immunizing against multiple toxins.

The recent use of Bacillus anthracis as a bioweapon has stimulated the search for novel anthrax antitoxins and vaccines that act rapidly with minimal adverse effects. B. anthracis produces a toxin composed of the receptor-binding moiety protective antigen (PA) and the enzymatic moieties edema factor and lethal factor. Current anthrax-vaccine strategies are based on targeting PA as the critical immunogen; however, these vaccines are molecularly ill-defined, can cause adverse reactions, and are administered in a lengthy immunization schedule (6 doses over 18 months). The development of a well-characterized vaccine that induces rapid immunity after a single injection remains an important goal. We have developed a novel, chimeric virus-like particle (VLP) capable of multivalent display of PA. In animal studies, rats (5/group) were immunized once with VLP-PA complex, PA alone, or VLP alone as a control. After four weeks the animals were challenged with anthrax lethal toxin. All rats that were immunized with the VLP-PA complex survived, whereas all other animals died. These results illustrate that this recombinant VLP platform, capable of multivalent display of PA, yields a significant advantage over monovalent, soluble PA as an immunogen for anthrax toxin, and represents a novel and highly effective reagent for protection against anthrax. An additional advantage of this VLP platform is its potential to be used to generate effective vaccines against pathogens other than anthrax, through the use of fusion protein technology to display other immunogens on the VLP. These pathogens include category A, B, and C agents, some of which represent major bioterrorism threats, such as ricin and botulinum neurotoxins. Further, by taking advantage of the multivalent display capability of the VLPs, it is possible that this approach could be used to generate combination vaccines, which could simultaneously immunize against anthrax, ricin, and botulinum toxins while circumventing the need for multiple dosings of immunogens..

References
No publications to date

Patent Status:
U.S. Patent Application Pending

License Terms:
Non-exclusive and Exclusive by Field of Use Licenses Negotiable

Reference_Number: S07001
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu

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Non-Nucleoside Reverse Transcriptase Inhibitors (S07014.pdf)

Inventors
Daniel Elleder, John Young, Thomas Baiga, Joseph Noel

Applications
HIV, Infection, Virus, Drug Development
Novel NNRTIs, compounds and pharmaceutical compositions for reducing HIV infection and replication.

Resistance of the human immunodeficiency virus (HIV) to HIV drugs has always been a major cause of treatment failure, leading to the use of combination therapy employing multiple anti-HIV agents, each usually having a different activity profile. The introduction of HAART therapy (Highly Active Anti-Retroviral Therapy), for example, has resulted in a significant reduction of morbidity and mortality in those HIV patients receiving it. HAART involves various combinations of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Current guidelines for antiretroviral therapy now recommend triple combination therapy regimens for initial treatment. Unfortunately, multi-drug therapies do not completely eliminate HIV, and long-term treatment usually results in multi-drug resistance. Half of the patients receiving anti-HIV combination therapy fail to respond fully, mainly because of resistance of the virus to one or more drugs used. The resistant virus is also carried over to newly infected individuals, who as a result have severely limited therapy options. Recently Salk Institute scientists identified a novel lead compound: a non-nucleoside reverse transcriptase inhibitor (NNTRI) that substantially reduces the activity of HIV-1 reverse transcriptase, thereby reducing HIV infection. This NNTRI also acts synergistically with one particular NRTI, zidovudine (or AZT), the first drug approved for the treatment of HIV. Structural Activity Relationship (SAR) analysis has identified additional, more potent derivatives of this compound, and experiments have confirmed their efficacy against wild-type and existing drug-resistant HIV-1 variants isolated from patients. The technology disclosed in the pending patent includes novel NNRTIs and compounds that can substantially inhibit HIV infection and replication and can be used in combination with other retriviral inhibitors. Also described are pharmaceutical compositions, prodrugs of the compounds, and methods for their creation, preparation and use. .

References
None to date

Patent Status:
U.S. Patent Application Filed 11/09/2007

License Terms:
Exclusive and Non-Exclusive Licenses Available

Reference_Number: S07014
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu