Claims
- 1. A method of identifying a potential drug target, comprising:
providing a database comprising nucleic acid or protein sequences, wherein said sequences are annotated with potential disease-associations of said sequences; providing an assay for measuring the disease characteristic of a disease potentially associated to any one of said sequences; decreasing expression or activity of at least one of the nucleic acid or protein sequences provided in the database; and determining whether the decreased expression or activity results in a change in said assay wherein a change in said assay is indicative that said nucleic acid or protein sequence is a potential drug target for the associated disease.
- 2. A method of identifying a potential drug target comprising:
providing a database comprising nucleic acid or protein sequences, wherein said sequences are annotated with potential disease-associations of said sequences; providing an assay for measuring the disease characteristic of a disease potentially associated to any one of said sequences; increasing expression or activity of at least one of the nucleic acid or protein sequences provided in the database; and determining whether the increased expression or activity results in a change in said assay wherein a change in said assay is indicative that said nucleic acid or protein sequence is a potential drug target for the associated disease.
- 3. A method of identifying a potential drug target comprising:
providing a database comprising nucleic acid or protein sequences, wherein said sequences are annotated with potential disease-associations of said sequences; determining differential expression or activity of said nucleic acid or protein sequences in a cell exhibiting a disease characteristic of a potential associated disease and a corresponding normal cell; decreasing expression or activity of said nucleic acid or protein sequences; and determining the effect of decreased expression or activity on said cell exhibiting disease characteristics of the associated disease, wherein a change in said disease characteristics is indicative that said nucleic acid or protein sequence is a potential drug target for said associated disease.
- 4. A method of identifying a potential drug target comprising:
providing a database comprising nucleic acid or protein sequences, wherein said sequences are annotated with potential disease-associations of said sequences; determining differential expression of said nucleic acid or protein sequences in a cell exhibiting disease characteristics of a potential associated disease and a corresponding normal cell; increasing expression or activity of said nucleic acid or protein sequence; and determining the effect of increased expression or activity on said cell exhibiting disease characteristics of the associated disease, wherein a change in said disease characteristics is indicative that said nucleic acid or protein sequence is a potential drug target for said associated disease.
- 5. The method of any one of claims 1-4, further comprising creating the database.
- 6. The method of any one of claims 1-4, wherein said database optionally contains domain analysis.
- 7. The method of claim 5, wherein creating the database comprises:
receiving a first set of information corresponding to a protein or nucleic acid; receiving a second set of information identifying a characteristic of said nucleic acid or protein; and conducting a clustering analysis to determine how said protein or nucleic acid should be clustered based on the first and second sets of information.
- 8. The method of claim 7, wherein the first set of information comprises sequence information and/or structural information.
- 9. The method of claim 7, wherein the second set of information comprises domain information.
- 10. The method of claim 9, wherein the second set of information indicates the presence or absence of one or more domains selected from the group of: Hect, Ring, Ubox, Fbox and PHD.
- 11. The method of any one of claims 1-4, wherein the nucleic acid or protein sequence is a human E3 sequence.
- 12. The method of any one of claims 1-4, wherein the potential disease associations are selected from the group consisting of viral diseases, proliferative disorders, and ubiquitin-mediated disorders.
- 13. The method of any one of claims 1-2, wherein the assay determines a disease characteristic of an associated disease.
- 14. The method of claim 13, wherein said disease characteristic is assessed by determining whether said protein interacts with an interacting-protein, and wherein said interacting-protein undergoes abnormal degradation in the disease characteristic.
- 15. The method of claim 13, wherein said disease characteristic is assessed by determining the cellular localization of said protein.
- 16. The method of claim 13, wherein said disease characteristic is assessed by determining the biological activity of said protein.
- 17. The method of claim 13, wherein the protein is a E3 protein.
- 18. The method of claim 17, wherein said disease characteristic is assessed by determining a biological activity of said E3 protein.
- 19. The method of claim 18, wherein the biological activity is the ligase activity of said E3 protein.
- 20. The method of claim 18, wherein said disease characteristic is assessed by determining whether said E3 interacts with a substrate that is ubiquitinated in the disease characteristic.
- 21. The method of claim 12, wherein said associated disease is a retroviral infection.
- 22. The method of claim 21, wherein said retroviral infection is HIV infection.
- 23. The method of claim 21, wherein said assay comprises determining the release of virus like particles (VLP) from infected cells.
- 24. The method of claim 23, wherein decreasing expression or activity of an E3 protein results in a change in the release of said VLPs.
- 25. The method of claim 24, wherein said E3 protein contains a WW domain.
- 26. The method of claim 24, wherein said E3 protein contains a HECT domain.
- 27. The method of claim 24, wherein said E3 protein contains a SH3 domain.
- 28. The method of claim 24, wherein said E3 protein contains a RING domain.
- 29. The method of any one of claims 1 or 3, wherein expression of said nucleic acid sequence is decreased using RNAi.
- 30. The method of any one of claims 1 or 3, wherein expression of said nucleic acid sequence is decreased using an antisense oligonucleotide construct.
- 31. The method of any one of claims 1 or 3, wherein expression of said nucleic acid sequence is decreased using ribozyme.
- 32. The method of any one of claims 1 or 3, wherein expression of said nucleic acid sequence is decreased using a DNA enzyme.
- 33. The method of claim 4, wherein the protein is a E3 protein.
- 34. The method of claim 33, wherein decreased expression of said E3 is indicative of a disease characteristic.
- 35. The method of claim 34, wherein said E3 is a tumor suppressor and the disease characteristic is tumorigenesis.
- 36. The method of claim 35, wherein an increase in expression or activity of said E3 protein results in a gain of function phenotype.
- 37. The method of claims 36, wherein said E3 is a potential drug target.
- 38. The method of claim 37, wherein the substrate of said E3 is also a potential drug target.
- 39. The method of claim 5, wherein access to the database is provided to subscribers.
- 40. A method for determining whether a test sequence is a potential drug target, comprising:
providing a database comprising nucleic acid or protein sequences, wherein said sequences are annotated with potential disease-associations of said sequences; comparing said test sequence to the sequences provided in said database and predicting potential disease associations; validating the predicted disease association by decreasing the activity of said nucleic acid or protein sequences; and updating the database to include the test sequence and associated annotations.
- 41. A method of identifying a therapeutic ribozyme for treating viral infections comprising:
(a) providing an E3 drug target for treating viral infections; (b) administering a ribozyme to decrease expression of said E3 in an infected cell; (c) determining the release of virus like particles from said infected cell; and wherein a decrease in the release of virus like particles is indicative that said ribozyme is a therapeutic ribozyme for treating said viral infections.
- 42. A method of identifying a therapeutic ribozyme for treating cancer comprising:
(a) providing an E3 drug target for treating cancer; (b) administering a ribozyme to decrease expression of said E3 in a tumor cell; (c) determining the rate of proliferation of said tumor cell; wherein a decrease in the rate of proliferation is indicative that said ribozyme is a therapeutic ribozyme for treating said proliferative diseases.
- 43. A method of identifying a therapeutic RNAi construct for treating viral infections comprising:
(a) providing an E3 drug target for treating viral infections; (b) administering a RNAi construct to decrease expression of said E3 in an infected cell; (c) determining the release of virus like particles from said infected cell; and wherein a decrease in the release of virus like particles is indicative that said RNAi construct is a therapeutic RNAi construct for treating said viral infections.
- 42. A method of identifying a therapeutic RNAi construct for treating cancer comprising:
(a) providing an E3 drug target for treating cancer; (b) administering a RNAi construct to decrease expression of said E3 in a tumor cell; (c) determining the rate of proliferation of said tumor cell; wherein a decrease in the rate of proliferation is indicative that said RNAi construct is a therapeutic ribozyme for treating said proliferative diseases.
- 43. A method of screening E3 proteins as potential drug targets, comprising:
selecting an E3 protein; decreasing expression or activity of said E3 protein in an viral-infected cell; determining the release of virus like particles upon decreasing the expression or activity of said E3; wherein a decrease the release of the virus like particles is indicative that said E3 protein is a potential drug target.
- 44. A method of creating a database of E3 proteins or nucleic acids, comprising:
receiving a first set of information corresponding to a protein or nucleic acid; receiving a second set of information identifying a characteristic of said nucleic acid or protein sequence; and conducting a clustering analysis to determine how said protein or nucleic acid sequences should be clustered based on the first and second sets of information.
- 45. The method of claim 44, wherein the first set of information comprises sequence information and/or structural information.
- 46. The method of claim 44, wherein the second set of information comprises domain information.
- 47. The method of claim 44, wherein the second set of information indicates the presence or absence of one or more domains selected from the group of: Hect, Ring, Ubox, Fbox and PHD.
- 48. The method of claim 47, wherein all protein and nucleic acid sequences comprising one or more domains selected from the group of: Hect, Ring, Ubox, Fbox and PHD are included within said database.
- 49. The method of claim 48, wherein the protein and nucleic acid sequences are further clustered based on the presence or absence of said domains.
- 50. The method of claim 48, wherein the protein and nucleic acid sequences are further clustered based on certain disease associations.
- 51. The method of claim 48, wherein the protein and nucleic acid sequences are further clustered based on the presence or absence of interacting motifs.
- 52. The method of claim 48, wherein the protein and nucleic acid sequences are further clustered based on one or more of the following: homology modeling, secondary structure, threading, transmembrane helices, signal peptide domains, and protein localization signals.
- 53. The method of claim 48, wherein said E3 sequences are evaluated as potential drug targets.
- 54. The method of claim 48, wherein said E3 sequences are screened is biological assays for testing disease associations.
- 55. A method of creating a database of proteins or nucleic acid sequences containing the RING domain, comprising:
receiving a first set of information corresponding to a protein or nucleic acid; receiving a second set of information identifying a characteristic of said nucleic acid or protein sequence; and conducting a clustering analysis to determine how said protein or nucleic acid sequences should be clustered based on the first and second sets of information.
- 56. The method of claim 55, wherein all protein and nucleic acid sequences comprising one or more Ring domains included within said database.
- 57. A method of screening an E3 protein as potential drug target, comprising:
selecting an E3 protein; decreasing expression or activity of said E3 protein in a tumor cell; determining the rate of proliferation of said tumor cell upon decreasing the expression or activity of said E3; wherein a decrease in the rate of proliferation is indicative that said E3 protein is a potential drug target.
- 58. A method of screening an E3 protein as a potential drug targets, comprising:
selecting an E3 protein; decreasing expression or activity of said E3 protein in a diseased cell; determining the effect of decreasing the expression or activity of said E3 on a Ubiquitin-mediated disorder; wherein a change is indicative that said E3 protein is a potential drug target.
- 59. The method of any one of claims 1 or 3, wherein expression or activity is decreased by using a dominant negative mutant.
- 60. The method of any one of claims 1 or 3, wherein expression or activity is decreased by using a small molecule.
- 61. A method of identifying a potential drug target for an associated disease comprising:
(a) conducting a structure-function analysis to determine domain information and/or structural information involved in disease associations; (b) providing a database comprising nucleic acid or protein sequence; (c) selecting sequences containing the domains and/or structural information relevant to disease associations; (d) providing an assay for measuring the disease characteristic; (e) decreasing the expression or activity of the nucleic acid or protein sequence selected in step (c); and (f) determining whether the decreased expression or activity results in change in said assay; wherein a change in the disease characteristic is indicative of a potential drug target.
- 62. A method of identifying a potential drug target for an associated disease comprising:
(a) conducting a structure-function analysis to determine domain information and/or structural information involved in disease associations; (b) providing a database comprising nucleic acid or protein sequence; (c) selecting sequences containing the domains and/or structural information relevant to disease associations; (d) providing an assay for measuring the disease characteristic; (e) increasing the expression or activity of the nucleic acid or protein sequence selected in step (c); and (f) determining whether the increased expression or activity results in change in said assay; wherein a change in the disease characteristic is indicative of a potential drug target.
- 63. The method of claim 61 or claim 62, wherein the protein and nucleic acid sequences are E3 sequences.
- 64. The method of claim 63, wherein the protein and nucleic acid sequences comprise one or more domains selected from the group of: Hect, Ring, Ubox, Fbox and PHD.
- 65. The method of claim 64, wherein the disease associations are selected from the group consisting of viral diseases, proliferative disorders, and ubiquitin-mediated disorders.
- 66. The method of claim 65, wherein the assay determines a disease characteristic of an associated disease.
- 67. The method of claim 66, wherein said disease characteristic is assessed by determining whether said protein interacts with an interacting-protein, and wherein said interacting-protein undergoes abnormal degradation in the disease characteristic.
- 68. The method of claim 66, wherein said disease characteristic is assessed by determining the cellular localization of said protein.
- 69. The method of claim 66, wherein said disease characteristic is assessed by determining whether said E3 interacts with a substrate that is ubiquitinated in the disease characteristic.
- 70. The method of claim 61, wherein expression of said nucleic acid sequence is decreased using RNAi construct.
- 71. The method of claim 61, wherein expression of said nucleic acid sequence is decreased using an antisense oligonucleotide construct.
- 72. The method of claim 61, wherein expression of said nucleic acid sequence is decreased using ribozyme.
- 73. The method of claim 61, wherein expression of said nucleic acid sequence is decreased using a DNA enzyme.
- 74. The method of claim 61, wherein activity of said protein is decreased by using a dominant negative mutant.
- 75. The method of claim 61, wherein expression or activity is decreased by using a small molecule.
- 76. The method of any one of claims 5, 44, or 55, wherein said database comprises at least 20, 25, 50, 75, 100, 125, 150, 200, 250, or 300 sequences.
RELATED APPLICATIONS
[0001] This application claims the benefit of the filing date of U.S. Provisional Application No. 60/331,701, filed Nov. 19, 2001, the specification of which is hereby incorporated by reference in its entirety.
Provisional Applications (1)
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Number |
Date |
Country |
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60331701 |
Nov 2001 |
US |