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(12) United States Patent (10) Patent No.: US 8,148,129 B2 Frankel Et Al

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(12) United States Patent (10) Patent No.: US 8,148,129 B2 Frankel Et Al US008148129B2 (12) United States Patent (10) Patent No.: US 8,148,129 B2 Frankel et al. (45) Date of Patent: Apr. 3, 2012 (54) GENERATION OF POTENT DOMINANT 6,824,978 B1 1 1/2004 Cox, III et al. NEGATIVE TRANSCRIPTIONAL 6,933,113 B2 8, 2005 Case et al. 6,979,539 B2 12/2005 Cox, III et al. INHIBITORS 7,013,219 B2 3/2006 Case et al. 7,070,934 B2 7/2006 Cox, III et al. (75) Inventors: Alan Frankel, Mill Valley, CA (US); 7,163,824 B2 1/2007 Cox, III et al. Robert Nakamura, San Francisco, CA 7,220,719 B2 5/2007 Case et al. (US); Chandreyee Das, Brookline, MA 7,235,354 B2 6/2007 Case et al. 7,262,054 B2 8/2007 Jamieson et al. (US); Ivan D’Orso, San Francisco, CA 7,273,923 B2 9/2007 Jamieson et al. (US); Jocelyn Grunwell, San Mateo, 2003, OO82552 A1* 5, 2003 Wolffe et al. ..................... 435/6 CA (US) (73) Assignee: The Regents of the University of OTHER PUBLICATIONS California, Oakland, CA (US) Cramer et al., Coupling of Transcription with Alternative Splicing: RNA Pol II Promoters Modulate SF2. ASF and 9G8 Effects on an (*) Notice: Subject to any disclaimer, the term of this Exonic Splicing Enhancer, Molecular Cell, 1999, 4:251-258.* patent is extended or adjusted under 35 Cama-Carvalho et al., Nucleocytoplasmic shuttling of heterodimeric U.S.C. 154(b) by 806 days. splicing factor U2AF, JBC. Published on Dec. 15, 2000 as Manu script M008759200.* (21) Appl. No.: 11/765,592 Rosonina et al., Gene Expression: The Close Coupling of Transcrip tion and Splicing, Current Biology, vol. 12, R319-R321, Apr. 30, (22) Filed: Jun. 20, 2007 20O2.* Peled-Zehavi et al., 2001, Molecular and Cellular Biology, (65) Prior Publication Data 21(15):5232-5241.* Zou et al., Journal of Biological Chemistry, 2000, 275(9):6051 US 2008/OO96813 A1 Apr. 24, 2008 6054.* Related U.S. Application Data * cited by examiner (60) Provisional application No. 60/817,927, filed on Jun. 30, 2006. Primary Examiner — Zachariah Lucas Assistant Examiner — Nicole Kinsey White (51) Int. Cl. (74) Attorney, Agent, or Firm — Morgan, Lewis & Bockius CI2N 7/00 (2006.01) LLP. Annette S. Parent (52) U.S. Cl. .................................................... 435/235.1 (58) Field of Classification Search ........................ None See application file for complete search history. (57) ABSTRACT (56) References Cited The present invention provides methods and compositions for regulating gene expression using transcription factors linked U.S. PATENT DOCUMENTS to proteins that localize to the transcriptional machinery. 6,599,692 B1 7/2003 Case et al. 6,607,882 B1 8/2003 Cox, III et al. 6,777, 185 B2 8, 2004 Case et al. 21 Claims, 22 Drawing Sheets U.S. Patent Apr. 3, 2012 Sheet 1 of 22 US 8,148,129 B2 U.S. Patent Apr. 3, 2012 Sheet 2 of 22 US 8,148,129 B2 (Je?JOdÐIHVLAlg) L-IS-L+ºº“AIG-L d oo co N. c\ v- O C O O (Ol X) ?had U.S. Patent Apr. 3, 2012 Sheet 4 of 22 US 8,148,129 B2 S S. No3 Št3 2 No 3 2iS Lo S. 3. Šy 2 to 3. SN ŠYS3 2Lo SN É O co w N % O SN co C C co o o C CO KC r CN uOle/NOW OO e/\ee U.S. Patent Apr. 3, 2012 Sheet 5 of 22 US 8,148,129 B2 Fig. 2a U.S. Patent Apr. 3, 2012 Sheet 6 of 22 US 8,148,129 B2 i. ... 2 U.S. Patent Apr. 3, 2012 Sheet 7 of 22 US 8,148,129 B2 P: S5P-CTD RNAP II P: Bot: Cy-GFP Mock input +Ab input +Ab input +Ab P: Cy-GFP P: Blot: P-TEFb. 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T COLO g wua Sto H-(S N - , cN it(T. - - - - SS d R w g So I Eul tr N - H- E" 9 o - Cl ver O) NS n d 9 rR SS < ess 352 <C S - H-is n H. L. On CN - H. P o - b N. & o g3 So e 3 ESg s" is it P - s LD ŠS CO Y Šo Yits inti CNP S - Y - c C) c d o S 2 o c r N uOeA3W po- eAlee 2 U.S. Patent Apr. 3, 2012 Sheet 20 of 22 US 8,148,129 B2 H Y Š sc ŠS N Š i RN SY Š S Š R- D Š SP a Ss Š H. H. Firsts ; : N uOSSeudx e/\lee U.S. Patent Apr. 3, 2012 Sheet 21 of 22 US 8,148,129 B2 O O O O d 00/ KO 3 S 3 00|| (u/6u) 72d U.S. Patent Apr. 3, 2012 Sheet 22 of 22 US 8,148,129 B2 O O O O O 00/ CO S. S. 00|| (u/6u) 7ad US 8,148,129 B2 1. 2 GENERATION OF POTENT DOMINANT and, employing the replication machinery of the host cells, NEGATIVE TRANSCRIPTIONAL produces new retroviral particles and advances the infection INHIBITORS to other cells. HIV appears to have a particular affinity for the human T4 lymphocyte cell, which plays a vital role in the CROSS-REFERENCES TO RELATED body’s immune system. HIV infection of these white blood APPLICATIONS cells depletes this white cell population. Eventually, the immune system is rendered inoperative and ineffective The present application claims the benefit of U.S. Ser. No. against various opportunistic diseases such as, among others, 60/817,927, filed Jun. 30, 2006, herein incorporated by ref. pneumocystic carini pneumonia, Kaposi's sarcoma, and can erence in its entirety. 10 cer of the lymph system. There are currently a number of antiviral drugs available to STATEMENT AS TO RIGHTS TO INVENTIONS combat the infection. These drugs can be divided into four MADE UNDER FEDERALLY SPONSORED classes based on the viral protein they target and their mode of RESEARCH ORDEVELOPMENT action. In particular, one class of Such antiviral drugs are 15 competitive inhibitors of the aspartyl protease expressed by This invention was made with government Support under HIV. Other agents are nucleoside reverse transcriptase inhibi Grant Nos. R01 AI29135 and R41CA 103407, awarded by the tors that behave as substrate mimics to halt viral clNA syn National Institutes of Health. The government has certain thesis. A class of non-nucleoside reverse transcriptase inhibi rights in this invention. tors inhibit the synthesis of viral clNA via a non-competitive (or uncompetitive) mechanism. Another class are drugs that BACKGROUND OF THE INVENTION block viral fusion. Used alone, these drugs show effectiveness in reducing viral replication. However, the effects are only The regulation of gene expression by transcription factors temporary as the virus readily develops resistance to all is a fundamental aspect of the physiology of all cells, whether known agents. prokaryotic or eukaryotic. In eukaryotic organisms, for 25 As indicated above, a number of critical points in the HIV instance, a variety of transcription factors govern cell growth, life cycle have been identified as possible targets for antiviral differentiation, and death. The appropriate spatial and tem drugs including (1) the initial attachment of the virion to the poral expression of specific transcription factors governs T4 lymphocyte or macrophage site; (2) the transcription of development. As examples, transcription factors such as Myc viral RNA to viral DNA (reverse transcriptase, RT); and (3) and E2F control progression through the cell cycle; home 30 the processing of gag-pol protein by HIV protease. An addi odomain, paired box, and forkhead transcription factors, tional, potentially attractive therapeutic target is transcription among others, are involved in embryonic development; p53 is of the HIV genome. Transcription of the HIV genome is involved with tumor suppression and cell death; steroid hor essential for replication of the virus after integration of viral mone receptors.
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