A patent review of sirtuin activators: An update

Expert Opinion on Therapeutic Patents

Volumn 22, Issue 4, 2012, Pages 355-367

  Villalba, José M ^a   De Cabo, Rafael ^b   Alcain, Francisco J ^c  

^a UNIVERSITY OF CÓRDOBA   (Spain)

^b NATIONAL INSTITUTE ON AGING   (United States)

^c UNIVERSITY OF CASTILLA LA MANCHA   (Spain)

Author keywords

aging; metabolic diseases; resveratrol; sirtuin activators; sirtuins

Indexed keywords

BORTEZOMIB; PLACEBO; RESVERATROL; SIRTUIN; SIRTUIN 1; SIRTUIN 2; SRT 1720; SRT 2140; SRT 2379; UNCLASSIFIED DRUG;

AGING; CLINICAL TRIAL; DRUG FORMULATION; HUMAN; HYPOTHALAMUS; IN VITRO STUDY; METABOLIC SYNDROME X; NONHUMAN; OBESITY; PATENT; PHYSIOLOGY; PROTEIN FUNCTION; REVIEW; SINGLE DRUG DOSE;

ANIMALS; ANTI-OBESITY AGENTS; DIETARY SUPPLEMENTS; DRUG DESIGN; ENZYME ACTIVATION; ENZYME ACTIVATORS; HETEROCYCLIC COMPOUNDS WITH 4 OR MORE RINGS; HUMANS; MOLECULAR STRUCTURE; PATENTS AS TOPIC; SIRTUIN 1; STILBENES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84859597181     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2012.669374     Document Type: Review

References (100)

1. Yang XJ, Seto E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol 2008;9:206-18 (Pubitemid 351301825)
2. Gray SG, Ekstrom TJ. The human histone deacetylase family. Exp Cell Res 2001;262:75-83 (Pubitemid 32980246)
3. Alcain FJ, Villalba JM. Sirtuin activators. Expert Opin Ther Patents 2009;19:403-14
4. Brittain D, Weinmann H, Ottow E. Recent advances in the medicinal chemistry of histone deacetylase inhibitors. Ann Rep Med Chem 2007;42:337-48
5. Sauve AA, Wolberger C, Schramm VL, et al. The biochemistry of sirtuins. Annu Rev Biochem 2006;75:435-65 (Pubitemid 44118039)
6. Imai S, Armstrong CM, Kaeberlein M, et al. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000;403:795-800 (Pubitemid 30111843)
7. Sauve AA. Sirtuin chemical mechanisms. Biochim Biophys Acta 2010;1804:1591-603
8. Du J, Zhou Y, Su X, et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 2011;334:806-9
9. Voelter-Mahlknecht S, Letzel S, Mahlknecht U. Fluorescence in situ hybridization and chromosomal organization of the human sirtuin 7 gene. Int J Oncol 2006;28:899-908
10. Vaziri H, Dessain SK, Ng Eaton E, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 2001;107:149-59 (Pubitemid 33035942)
11. Ford E, Voit R, Liszt G, et al. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev 2006;20:1075-80
12. North BJ, Marshall BL, Borra MT, et al. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell 2003;11:437-44 (Pubitemid 36293837)
13. Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J 2007;404:1-13 (Pubitemid 46788079)
14. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 2000;289:2126-8
15. Rogina B, Helfand SL. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci USA 2004;101:15998-6003 (Pubitemid 39507916)
16. Boily G, Seifert EL, Bevilacqua L, et al. SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS One 2008;3:e1759
17. Imai S, Guarente L. Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends Pharmacol Sci 2010;31:212-20
18. Someya S, Yu W, Hallows WC, et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 2010;143:1-11 In this paper authors demonstrate that animals lacking SIRT3 are not protected by CR against age-related hearing loss, highlighting the importance of sirtuin activity for maintaining healthy aging.
19. Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004;305:390-2 (Pubitemid 38938153)
20. Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425:191-6 The first report to demonstrate that RSV mimics caloric restriction by stimulating Sir2 and extending lifespan in yeast.
21. Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 2008;8:157-68 These authors have reported that RSV induces gene expression patterns in multiple tissues that parallel those induced by CR in mice. Although the animals showed a marked reduction in signs of aging, they did not live longer when fed a standard diet and treated with RSV beginning at 12 months of age.
22. Barger JL, Kayo T, Pugh TD, et al. Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart. Exp Gerontol 2008;43:859-66 Mice were fed with a diet supplemented with a commercially available nutraceutical mixture containing RSV, or with a diet supplemented with low doses of RSV. The increase in the expression of genes that protect heart from aging processes was determined.
23. Burnett C, Valentini S, Cabreiro F, et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 2011;477:482-5 This article underscores the importance of controlling for genetic background and for the mutagenic effects of transgene insertions in studies of genetic Sir2 effects on lifespan.
24. Bauer J, Antosh M, Chang C, et al. Comparative transcriptional profiling identifies takeout as a gene that regulates life span. Aging (Albany NY) 2010;2:298-310 Using organisms of the same genetic background, it was found that both CR and dSir2 overexpression produced changes in a number of genes. One of these genes, takeout, was also increased in four other lifespan extending conditions, and its increased expression extended lifespan.
25. Wang C, Wheeler CT, Alberico T, et al. The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster. Age (Dordr) DOI: 10.1007/s11357-011-9332-3 2011;PMID 22083438
26. Brunet A, Sweeney LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004;303:2011-15 (Pubitemid 38393275)
27. Rodgers JT, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434:113-18 These results implicate SIRT1 in the basic pathways of energy homeostasis through the deacetylation of PGC-1α.
28. Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 2004;23:2369-80 (Pubitemid 38954844)
29. Silva JP, Wahlestedt C. Role of Sirtuin 1 in metabolic regulation. Drug Discov Today 2010;15:781-91
30. Canto C, Jiang LQ, Deshmukh AS, et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 2010;11:213-19
31. Hallows WC, Yu W, Denu JM. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J Biol Chem 2012;287:3850-8
32. Iwabu M, Yamauchi T, Okada-Iwabu M, et al. Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 2010;464:1313-19
33. Purushotham A, Xu Q, Li X. Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding. FASEB J 2012;26:656-67
34. Wang RH, Kim HS, Xiao C, et al. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest 2011;121:4477-90
35. Baur JA. Resveratrol, sirtuins, and the promise of a DR mimetic. Mech Ageing Dev 2010;131:261-9 This excellent review summarizes recent research on RSV, sirtuins and their potential to mimic beneficial effects of calorie restriction.
36. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 2010;5:253-95
37. Civitarese AE, Carling S, Heilbronn LK, et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 2007;4:e76 One of the first biochemical studies of CR on human metabolism. Authors demonstrate that caloric restriction improves mitochondrial function in young, non-obese adults by upregulation of SIRT1.
38. Clark SJ, Falchi M, Olsson B, et al. Association of Sirtuin 1 (SIRT1) gene SNPs and transcript expression levels with severe obesity. Obesity (Silver Spring) 2012;20:178-85 This is the first report correlating SIRT1 SNPs to both obesity and lower BMI in humans. Also, transcript levels of SIRT1 were found to be significantly higher in lean compared with obese siblings.
39. Ramadori G, Lee CE, Bookout AL, et al. Brain SIRT1: anatomical distribution and regulation by energy availability. J Neurosci 2008;28:9989-96
40. Sasaki T, Kim HJ, Kobayashi M, et al. Induction of hypothalamic Sirt1 leads to cessation of feeding via agouti-related peptide. Endocrinology 2010;151:2556-66 A link between SIRT1 expression in mediobasal hypothalamic neurons and decreased food intake is mediated by FOXO1-dependent expression of orexigenic neuropeptide AgRP.
41. Ramadori G, Fujikawa T, Fukuda M, et al. SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab 2010;12:78-87 SIRT1 expression in POMC neurons is required for normal energy expenditure adaptations and leptin's molecular and physiological actions against diet-induced obesity.
42. Knight CM, Gutierrez-Juarez R, Lam TK, et al. Mediobasal hypothalamic SIRT1 is essential for resveratrol's effects on insulin action in rats. Diabetes 2011;60:2691-700
43. Jiang M, Wang J, Fu J, et al. Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat Med 2011;18:153-8
44. Jeong H, Cohen DE, Cui L, et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med 2011;18:159-65
45. Rutanen J, Yaluri N, Modi S, et al. SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity. Diabetes 2010;59:829-35 Reduced SIRT1 expression correlates with reduced energy expenditure in insulin-sensitive tissues from diabetic patients.
46. Timmers S, Konings E, Bilet L, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 2011;14:612-22 Consumption of ResVida, a RSV-containing formulation, for 30 days induces changes on the metabolic profile in healthy obese humans, mimicking the effects of CR.
47. Swindell WR. Gene expression profiling of long-lived dwarf mice: longevity-associated genes and relationships with diet, gender and aging. BMC Genomics 2007;8:353
48. Weindruch R, Kayo T, Lee CK, et al. Microarray profiling of gene expression in aging and its alteration by caloric restriction in mice. J Nutr 2001;131:918S-23S (Pubitemid 32199170)
49. Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004;430:686-9 (Pubitemid 39061685)
50. Celotti E, Ferrarini R, Zironi R, et al. Resveratrol content of some wines obtained from dried valpolicella grapes: recioto and amarone. J Chromatogr A 1996;730:47-52 (Pubitemid 26141922)
51. Walle T, Hsieh F, Delegge MH, et al. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos 2004;32:1377-82 (Pubitemid 39564557)
52. Vang O, Ahmad N, Baile CA, et al. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One 2011;6:e19881
53. Barger JL, Kayo T, Vann JM, et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE 2008;3:e2264 This paper shows that a dose of dietary RSV lower than suspected also mimicked the effects of caloric restriction in insulin-mediated glucose uptake in muscle. Gene expression profiles suggest that both caloric restriction and RSV may retard some aspects of aging.
54. Dsm Ip Assets Bv. Novel use of nutraceutical compositions comprising resveratrol. WO2007042272; 2007
55. Sirtris Pharma. Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders. WO2007008548; 2007
56. Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006;444:337-42 This study demonstrated that RSV prevents the deleterious effects of excess caloric intake and shifts the physiology toward that of mice present on a standard diet increasing significantly their survival. (Pubitemid 44764104)
57. Wong RH, Howe PR, Buckley JD, et al. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis 2011;21:851-6
58. Resveratrol Partners Dietary supplement and method of processing same. WO2005099761; 2005
59. Pilegaard H, Neufer PD. Transcriptional regulation of pyruvate dehydrogenase kinase 4 in skeletal muscle during and after exercise. Proc Nutr Soc 2004;63:221-6 (Pubitemid 38787469)
60. Mukherjee S, Ray D, Lekli I, et al. Effects of Longevinex (modified resveratrol) on cardioprotection and its mechanisms of action. Can J Physiol Pharmacol 2010;88:1017-25
61. Juhasz B, Mukherjee S, Das DK. Hormetic response of resveratrol against cardioprotection. Exp Clin Cardiol 2010;15:e134-8
62. Juhasz B, Das DK, Kertesz A, et al. Reduction of blood cholesterol and ischemic injury in the hypercholesteromic rabbits with modified resveratrol, longevinex. [corrected]. Mol Cell Biochem 2011;348:199-203
63. Fujitaka K, Otani H, Jo F, et al. Modified resveratrol longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment. Nutr Res 2011;31:842-7 Consumption of Longevinex, a RSV-containing formulation, for 3 months specifically improves endothelial function in subjects with metabolic syndrome.
64. Sirtris Pharma. Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders. WO2007008548; 2007
65. Smith JJ, Kenney RD, Gagne DJ, et al. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst Biol 2009;3:31
66. Howells LM, Berry DP, Elliott PJ, et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases - safety, pharmacokinetics, and pharmacodynamics. Cancer Prev Res (Phila) 2011;4:1419-25
67. Available from: Http://Www. Fiercebiotech.Com/Story/Weak-Efficacy- Renal-Risks-Force-Gsk-Dump- Resveratrol-Program/2010-12- 01#Ixzz1f6apohzc [Accessed 30 November 2011]
68. Bemis JE, Vu CB, Xie R, et al. Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators. Bioorg Med Chem Lett 2009;19:2350-3
69. Milne JC, Lambert PD, Schenk S, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007;450:712-16 The authors identified putative activators of human SIRT1 by a high-throughput screening of a large collection of small molecules, which mimic the health benefits of RSV but are 1000 times more effective. These compounds improved the response to insulin, reduced blood glucose levels and increased the number and activity of mitochondria in the diet-induced obese and genetically obese mice.
70. Vu CB, Bemis JE, Disch JS, et al. Discovery of imidazo[1,2-b]thiazole derivatives as novel SIRT1 activators. J Med Chem 2009;52:1275-83
71. Feige JN, Lagouge M, Canto C, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab 2008;8:347-58 Authors demonstrate that SRT1720, a synthetic activator of sirtuin, protects from diet-induced obesity and insulin resistance, validating SIRT1 as a target for the treatment of metabolic syndrome.
72. Sirtris Pharma. Sirtuin modulating compounds. US8044198; 2009
73. Funk JA, Odejinmi S, Schnellmann RG. SRT1720 induces mitochondrial biogenesis and rescues mitochondrial function after oxidant injury in renal proximal tubule cells. J Pharmacol Exp Ther 2010;333:593-601
74. Yamazaki Y, Usui I, Kanatani Y, et al. Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice. Am J Physiol Endocrinol Metab 2009;297:E1179-86
75. Minor RK, Baur JA, Gomes AP, et al. SRT1720 suppresses apoptosis and restores a more normal gene expression profile indicative of reduced inflammation in the livers of mice fed a high-fat diet. Sci Rep 2011;1:10-1038/srep00070 In this extensive study, authors report that the synthetic compound SRT1720 provokes lifespan extension accompanied by health benefits and the prevention of multiple age-related diseases in mice fed a high-fat diet.
76. Chauhan D, Bandi M, Singh AV, et al. Preclinical evaluation of a novel SIRT1 modulator SRT1720 in multiple myeloma cells. Br J Haematol 2011;155:588-98 In a preclinical evaluation, SRT1720 showed growth inhibitory effect in a human plasmacytoma xenograft mouse model, with no toxicity observed during treatment of mice.
77. Sirtirs Pharma. Oxazolopyridine derivatives as SIRTUIN modulators. CN101316853; 2008
78. Sirtris Pharma. Imidazo [2, 1-b] thiazole derivatives as sirtuin modulating compounds. WO2007019344; 2007
79. Van Der Meer A, Scicluna B, Lin J, et al. The first demonstration of clinical activity by a small molecule sirt1 activator: srt2104 reduces cytokine release and coagulation activation in a human endotoxemia model. 10th World Congress on Inflammation; Paris; 2011
80. Mai A, Valente S, Meade S, et al. Study of 1,4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors. J Med Chem 2009;52:5496-504
81. Qin W, Yang T, Ho L, et al. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem 2006;281:21745-54 (Pubitemid 44181878)
82. Yang T, Chan NY, Sauve AA. Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. J Med Chem 2007;50:6458-61 (Pubitemid 350309084)
83. Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem 2005;280:17187-95 This paper, together with ref. 71, demonstrates that RSV activation of human SIRT1 requires the use of acetylated peptides conjugated to a non-physiological fluorophore; however, no activation by RSV is found when the assays are carried out with unconjugated peptides.
84. Kaeberlein M, Mcdonagh T, Heltweg B, et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem 2005;280:17038-45 (Pubitemid 41389166)
85. Beher D, Wu J, Cumine S, et al. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des 2009;74:619-24
86. Huber JL, Mcburney MW, Distefano PS, et al. SIRT1-independent mechanisms of the putative sirtuin enzyme activators SRT1720 and SRT2183. Future Med Chem 2010;2:1751-9
87. Pacholec M, Bleasdale JE, Chrunyk B, et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 2010;285:8340-51 Authors demonstrate, through several biochemical and biophysical methods, that presence of the fluorophore in the peptide substrate is a crucial factor in the activation by small molecules seen in these assays. No activation was seen when the assays were carried out with native substrates. Moreover, all tested compounds hit multiple targets, supporting against their suitability as pharmacological tools.
88. Cen Y, Youn DY, Sauve AA. Advances in characterization of human sirtuin isoforms: chemistries, targets and therapeutic applications. Curr Med Chem 2011;18:1919-35
89. Dai H, Kustigian L, Carney D, et al. SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator. J Biol Chem 2010;285:32695-703
90. Kim EJ, Kho JH, Kang MR, et al. Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Mol Cell 2007;28:277-90
91. Autiero I, Costantini S, Colonna G. Human sirt-1: molecular modeling and structure-function relationships of an unordered protein. PLoS One 2009;4:e7350
92. Auld DS, Lovell S, Thorne N, et al. Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124. Proc Natl Acad Sci USA 2010;107:4878-83
93. Sirtris Pharma. Sirtuin activators and activation assays. WO2011130595; 2011
94. Cornell Univ. Activation and activators of SIRT5. WO2011081942; 2011
95. Smith BC, Hallows WC, Denu JM. A continuous microplate assay for sirtuins and nicotinamide-producing enzymes. Anal Biochem 2009;394:101-9
96. Feng Y, Wu J, Chen L, et al. A fluorometric assay of SIRT1 deacetylation activity through quantification of nicotinamide adenine dinucleotide. Anal Biochem 2009;395:205-10
97. Csiszar A, Labinskyy N, Podlutsky A, et al. Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. Am J Physiol Heart Circ Physiol 2008;294:H2721-35
98. +/ NADH ratio.
99. + and the activation of SIRT1, through a mechanism involving AMPK.
100. Revollo JR, Grimm AA, Imai S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem 2004;279:50754-63 (Pubitemid 40017813)