(19) TZZ _ __T (11) EP 2 781 219 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 24.09.2014 Bulletin 2014/39 A61K 31/7004 (2006.01) A61P 29/00 (2006.01) (21) Application number: 13160443.1 (22) Date of filing: 21.03.2013 (84) Designated Contracting States: • Wagner, Oswald AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 1090 Vienna (AT) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • Nagy, Csörsz PL PT RO RS SE SI SK SM TR 1090 Vienna (AT) Designated Extension States: • Marculescu, Rodrig BA ME 1090 Vienna (AT) (71) Applicant: Medizinische Universität Wien (74) Representative: Sonn & Partner Patentanwälte 1090 Vienna (AT) Riemergasse 14 1010 Wien (AT) (72) Inventors: • Haschemi, Arvand 1090 Vienna (AT) (54) Use of sedoheptulose for prevention or treatment of inflammation (57) The invention discloses sedoheptulose for use in the prevention or treatment of inflammation. EP 2 781 219 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 781 219 A1 2 Description ourful fruits and vegetables, oily fish (which contain high- er levels of omega-3 fatty acids), nuts, seeds and certain [0001] The technical field of the present invention is spices, such as ginger. Extra-virgin olive oil contains the the prevention or treatment of inflammation. chemical oleocanthal that acts similarly to ibuprofen. [0002] Inflammation is part of the complex biological 5 Omega-3 fatty acids have been shown to disrupt inflam- response of vascular tissues to harmful stimuli, such as mation cell signaling pathways by binding to the GPR120 pathogens, damaged cells, or irritants. The classical receptor. signs of acute inflammation are pain, heat, redness, [0007] However, there is still a need for prevention and swelling and loss of function. Inflammation is a protective treatment of inflammation, especially chronic inflamma- attempt by the organism to remove the injurious stimuli 10 tion. Such prevention and treatment should be provided and to initiate the healing process. Inflammation is a ster- without severe side effects or, preferably, without the risk eotyped response, and therefore it is considered as a for long term adverse developments, such as addiction, mechanism of innate immunity, as compared to adaptive metabolic disorders, declining efficacy, etc.. immunity, which is specific for each pathogen. [0008] Therefore, the present invention provides se- [0003] Inflammation can be classified as either acute 15 doheptulose for use in the prevention or treatment of in- or chronic. Acute inflammation is the initial response of flammation. the body to harmful stimuli and is achieved by the in- [0009] Sedoheptulose (CAS number: 3019-74-7; creased movement of plasma and leukocytes (especially PubChem: 5459879; ChemSpider: 4573620; MeSH: se- granulocytes) from the blood into the injured tissues. A doheptulose; ChEBI: CHEBI:16802) or D-altro-heptu- cascade of biochemical events propagates and matures 20 lose is a ketoheptose - a monosaccharide with seven the inflammatory response, involving the local vascular carbon atoms and a ketone functional group. It is one of system, the immune system and various cells within the the few heptoses found in nature. Sedoheptulose is pro- injured tissue. Prolonged inflammation, known as chronic ducible by extraction from natural sources or by chemical inflammation, leads to a progressive shift in the type of synthesis. It can be purified to high purity degrees (e.g. cells present at the site of inflammation and is character- 25 > 90 % purity, preferably > 95 % purity, more preferred ized by simultaneous destruction and healing of the tis- > 99 % purity, especially > 99.9 % purity). sue from the inflammatory process. [0010] Sedoheptulose is a relatively unknown metab- [0004] Inflammatory abnormalities (inflammatory dis- olite compared to its phosphorylated form, sedoheptu- orders) are a large group of disorders which underlie a lose-7-phosphate (S7P), which is recognised as an in- vast variety of human diseases. The immune system is 30 termediate molecule of primary glucose metabolism. The often involved with inflammatory disorders, demonstrat- natural existence of sedoheptulose, a ketoheptose, was ed in both allergic reactions and some myopathies, with first reported in plants and was subsequently identified many immune system disorders resulting in abnormal in human urine, blood spots and recently, within mouse inflammation. Non-immune diseases with etiological or- cells. S7P is derived from the transketolase-catalysed igins in inflammatory processes include cancer, athero- 35 conversion of ribose-5-phosphate (R5P) and xylulose-5- sclerosis and ischaemic heart disease. Examples of dis- phosphate (X5P). This reaction occurs in the non-oxida- orders associated with inflammation include acne vul- tive arm of the pentose phosphate pathway and gener- garis, asthma, autoimmune diseases, celiac disease, ates glyceraldehyde-3-phosphate (G3P), a key glycolytic chronic prostatitis, glomerulonephritis, hypersensitivi- intermediate, in addition to S7P. G3P and S7P are also ties, inflammatory bowel diseases, pelvic inflammatory 40 produced by transaldolase using fructose-6-phosphate disease, reperfusion injury, rheumatoid arthritis, sar- (F6P) and erythrose-4-phosphate (E4P) as substrates. coidosis, transplant rejection, vasculitis, interstitial cysti- S7P is thus a crucial intermediate in the non-oxidative tis, atherosclerosis, allergy, myopathies, leucocyte de- PPP and S7P bioavailability therefore contributes to cel- fects and cancer. lular carbon flux. Recently, data from several groups [0005] Medical treatment of acute and chronic infec- 45 have indicated that sedoheptulose kinase may also pro- tions has been performed with corticosteroids or non- duce S7P by direct phosphorylation of sedoheptulose steroidal anti-inflammatory drugs (NSAIDs). (Haschemi et al., Cell Metab. 15 (2012), 813-826). This [0006] Also anti-inflammatory foods have been sug- finding demonstrated the unexpected existence of an ad- gested to treat or prevent inflammation. Prostaglandins ditional carbon source, sedoheptulose, which actively are hormone-like substances that affect the body in va- 50 participates in cellular carbon metabolism. riety of ways, also regulating inflammatory mediation. An [0011] Free sedoheptulose can either be diet-derived anti-inflammatory diet includes less food that create in- from fruits and vegetables or formed enzymatically by flammation-causing prostaglandins (PGE2) in the body, the dephosphorylation of endogenously produced S7P. and more foods that create anti-inflammatory prostag- Thus far, no specific sedoheptulose transporter or S7P- landins (PGE1 and PGE3). Suggested diets to prevent 55 specfic phosphatase has been reported. Other bio-active inflammation include those rich in vegetables and low in heptoses include the phenolic compound 7-O-Galloyl- simple carbohydrates and fats, such as saturated fats sedoheptulose (GS), mannoheptulose and glycohep- and trans-fats. Anti-inflammatory foods include most col- tose. GS was reported to be protective in diabetic injury 2 3 EP 2 781 219 A1 4 of the kidney by alleviating inflammatory responses. els were not changed by CARKL perturbation. The S7P Mannoheptulose (various patents pending) is an isomer levels were not changed by overexpression but de- of sedoheptulose and a potent hexokinase inhibitor com- creasedsignificantly by CARKL loss,indicating sedohep- monly found in avocados. Glycoheptose, although no tulose phosphorylation as a rate-limiting factor for glyc- chemical nature of this compound remains unidentified, 5 olysis-derived G3P distribution. Therefore, the regulation has been shown to serve as accessible carbohydrate of S7P availability might be the mechanism by which source in rabbits. Sedoheptulosan is the anhydride of CARKL or excessive amounts of sedoheptulose modu- sedoheptulose and might also serve as source for free late cellular metabolism. sedoheptulose. [0016] The present invention is therefore directed to [0012] Free sedoheptulose can be isolated, e.g. from 10 use of C7, e.g. to balance C6-(over)consumption, obes- the plant sedum spectabile and has been previously re- ity, diabetes, immune function and - generally - verte- ported to contain high amounts of heptose-carbohy- brate’s energy utilization. The C7 supplement therefore drates. also provides an effective strategy to manage physiolog- [0013] Sedoheptulose kinase phosphorylates free se- ical redox-regulation and thereby also related disorders. doheptulose, which enables cells to directly route sedo- 15 With the present invention, it turned out that, both, high heptulose to carbohydrate metabolism, similar to hexoki- sedoheptulose and high sedoheptulose kinase results in nase and glucose. According to the present invention, enhanced sedoheptulose turn-over. Moreover, tissue ex- sedoheptulose is a direct carbon source that feeds pri- pression of sedoheptulose kinase reveals that metabolic mary carbohydrate catabolism and anabolism, whereup- organs such as liver or adipose-tissue have the capability on CARKL constitutes its entry point. Sedoheptulose can 20 to consume sedoheptulose. Additionally, brown-adipose therefore surprisingly be compared to glucose and fruc- tissue (burns high amounts of lipids) express significantly tose because these compounds all exist as free carbo- more (∼2,5 x) sedoheptulose kinase than white-adipose hydrates and phosphorylated forms. To enter metabo- tissue. lism, free carbohydrates are energetically activated by [0017] Sedoheptulose (and/or other heptoses),