Patent
Use of SIRT1 activators or inhibitors to modulate an immune response
| العنوان: | Use of SIRT1 activators or inhibitors to modulate an immune response |
|---|---|
| Patent Number: | 8,748,464 |
| تاريخ النشر: | June 10, 2014 |
| Appl. No: | 12/838247 |
| Application Filed: | July 16, 2010 |
| مستخلص: | The present disclosure provides a method of increasing an immune response in an individual, the method involving administering to an individual in need thereof an inhibitor of SIRT1. The present disclosure provides a method of reducing an immune response, e.g., to treat chronic immune hyperactivity, the method generally involving administering to an individual in need thereof an activator of SIRT1. The present disclosure provides a method of modulating activation and differentiation of CD4+ T cells. |
| Inventors: | Verdin, Eric M. (San Francisco, CA, US); Ott, Melanie (San Francisco, CA, US); Kwon, Hye-Sook (San Mateo, CA, US); Lim, Hyungwook (San Francisco, CA, US) |
| Assignees: | The J. David Gladstone Institutes (San Francisco, CA, US) |
| Claim: | 1. A method of treating chronic immune hyperactivity in an individual, the method comprising administering to an individual having chronic immune hyperactivity an effective amount of a SIRT1 activator, wherein the SIRT1 activator is a compound of the formula: [chemical expression included] or a salt thereof, wherein R 19 is selected from: [chemical expression included] wherein: each Z 10 , Z 11 , Z 12 and Z 13 is independently selected from N, CR 20 or CR 1 ′; and each Z 14 , Z 15 and Z 16 is independently selected from N, NR 1 ′, S, O, CR 20 , or CR 1 ′, wherein: zero to two of Z 10 , Z 11 , Z 12 or Z 13 are N; at least one of Z 14 , Z 15 and Z 16 is N, NR 1 ′, S or O; zero to one of Z 14 , Z 15 and Z 16 is S or O; zero to two of Z 14 , Z 15 and Z 16 is N or NR 1 ′; zero to one R 30 is a solubilizing group; and zero to one R 1 ′ is an optionally substituted C 1 -C 3 straight or branched alkyl; each R 20 is independently selected from H or a solubilizing group; R 21 is selected from —NR 1 ′—C(O)—, —NR 1 ′—S(O) 2 —, —NR 1 ′—C(O)—NR 1 ′—, —NR 1 ′—C(S)—NR 1 ′—NR 1 ′—C(S)— NR 1 ′—CR 1 ′R 1 ′—, —NR 1 ′—C(O)—CR 1 ′R 1 ′—NR 1 ′—, —NR 1 ′—C(═NR 1 ′)—NR 1 ′—, —C(O)—NR 1 ′—C(O)—NR 1 ′—, —CR 1 ′R 1 ′—, —NR 1 ′—C(O)—C(O)—CR 1 ′═CR 1 ′—, —NR 1 ′—S(O) 2 —NR 1 ′–—NR 1 ′—C(O)—NR 1 ′—S(O) 2 —, —NR 1 ′—CR 1 ′R 1 ′—C(O)—NR 1 ′—, —CR 1 ′R 1 ′—C(O)—NR 1 ′—, —NR 1 ′—C(O)—CR 1 ′═CR 1 ′—CR 1 ′R 1 ′—, —NR 1 ′—C(═N—CN)—NR 1 ′—, —NR 1 ′—C(O)—CR 1 ′R 1 ′—O—, —NR 1 ′—C(O)—CR 1 ′R 1 —CR 1 ′R 1 ′—O—, —NR 1 ′—S(O) 2 —CR 1 ′R 1 ′—, —NR 1 ′—S(O) 2 —CR 1 ′R 1 ′—CR 1 ′R 1 ′—, —NR 1 ′— C(O)—CR 1 ′R 1 ′—; —NR 1 ′—C(O)—CR 1 ′R′ 1 —CR 1 ′R′ 1 —, —NR 1 ′—C(S)—NR 1 ′—CR 1 ′R′ 1 —CR 1 ′R′ 1 —, —NR 1 ′—C(O)—O—, [chemical expression included] wherein each R 1 ′ is independently selected from H or optionally substituted C 1 -C 3 straight or branched alkyl; and R 31 is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein the chronic immune hyperactivity results from an immunodeficiency virus infection. |
| Claim: | 2. The method of claim 1 , wherein the individual is a human. |
| Claim: | 3. The method of claim 1 , wherein the immunodeficiency virus infection is a human immunodeficiency virus-1 (HIV-1) infection. |
| Claim: | 4. The method of claim 3 , further comprising administering to the individual at least one additional therapeutic agent that treats the HIV-1 infection. |
| Claim: | 5. The method of claim 1 , wherein the SIRT1 activator is a selective SIRT1 activator. |
| Claim: | 6. The method of claim 1 , wherein the SIRT1 activator is a compound of the formula: [chemical expression included] |
| Claim: | 7. The method of claim 1 , wherein the SIRT1 activator is administered orally. |
| Current U.S. Class: | 514/366 |
| Patent References Cited: | 7345178 March 2008 Nunes et al. 2005/0209300 September 2005 Napper et al. 2007/0043050 February 2007 Nunes et al. 2007/0105109 May 2007 Geesaman et al. 2007/0190073 August 2007 Tuck et al. 2008/0255382 October 2008 Andrus et al. 2009/0012080 January 2009 Bemis et al. 2010/0061984 March 2010 Greene et al. |
| Other References: | Milne et al “Small rnoiecuie activators of SIRT1 as therapeutics for the treatment of type 2 diabetes,” (2007) Nature 450:712-716. cited by applicant Ott et al., “Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway,” (1997) Science 275:1481-1485. cited by applicant Nayagam et al., “SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents,” (2006) J. Biomol. Screening 11:959-967. cited by applicant Ott, M. “Role of SIRT1 in T cell Hyperacitivation during HIV infection California HIV/AIDS Research Program,” 2008 http://chrp.ucop.edu/funded—research/abstracts/2007—ott.html (2007), para 1-3. cited by applicant Feige et al., “Specific SIRT1 Activation Mimics Low Energy Levels and Protects against Diet-Induced Metabolic Disorders by Enhancing Fat Oxidation,” (2008) Cell Metabolism 8:347-358. cited by applicant Sakamoto, K. “Silencing Metabolic Disorders by Novel SIRT1 Activators,” (2008) Cell Metabolism 7:3-4. cited by applicant Pacholec et al., “SRT1720, SRT2183, SRT1460, and Resveratrol are not Direct Activators of SIRT1,” Published on Jan. 8, 2010 as Manuscript M109.088682 The latest version is at http://www.jbc.org/cgi/doi/10.1074/jbc.M109.088682—25 pages. cited by applicant Sundrud et al., “Synergistic and combinatorial control of T cell activation and differentiation by transcription factors,” ScienceDirect www.sciencedirect.com, Current Opinion in Immunology (2010) 22:1-7. cited by applicant Tao et al., “Deacetylase inhibition promotes the generation and function of regulatory T cells,” (2007) Nat. Med. 13 (11):1299-1307. cited by applicant Saouaf et al., “Deacetylase inhibition increases regulatory T cell function and decreases incidence and severity of collagen-induced arthritis,” (2009) Exp. Mol. Pathol. 87:99-104. cited by applicant Van Loosdregt et al., “Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization” (2010) Blood 115(5):965-974. cited by applicant Wang et al., “Using histone deacetylase inhibitors to enhance Foxp3+ regulatory T-cell function and induce allograft tolerance,” (2009) Immunol. Cell Biol. 87:195-202. cited by applicant Pagans, et al. “SIRT1 Regulates HIV Transcription via TAT Deacetylation”, PLoS Biology, Feb. 2005, vol. 3, Issue 2, pp. 0210-0220. cited by applicant |
| Assistant Examiner: | Betton, Timothy E |
| Primary Examiner: | Padmanabhan, Sreeni |
| Attorney, Agent or Firm: | Borden, Paula A. Bozicevic, Field & Francis LLP. |
| رقم الانضمام: | edspgr.08748464 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |