WO2003099315A1 - A pharmaceutical composition comprising a retro-iverso isomer peptide - Google Patents
A pharmaceutical composition comprising a retro-iverso isomer peptide Download PDFInfo
- Publication number
- WO2003099315A1 WO2003099315A1 PCT/KR2003/001017 KR0301017W WO03099315A1 WO 2003099315 A1 WO2003099315 A1 WO 2003099315A1 KR 0301017 W KR0301017 W KR 0301017W WO 03099315 A1 WO03099315 A1 WO 03099315A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- val
- peptide
- group
- pharmaceutical composition
- tyr
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to therapeutic peptides that possess inhibitory activity towards elevation of serum triglyceride (triacylglycerol) levels, an unavoidable result that occurs upon ingestion of meals containing high composition of fat.
- Administration of such peptides before or concomitantly with meals allows for less net absorption of fatty acids into the system, thereby contributing to the prevention of various known cardiovascular diseases as well as obesity-related ailments in general.
- the present invention provides a pharmaceutical composition or a food composition for administration to a human or an animal comprising a retro-inverso isomer peptide as an active component.
- a pharmaceutical composition for administration to a human or an animal comprising , as an active component, a peptide selected from the group consisting of D-Pro D-Tyr D-Val D-Val, D-Pro D-Tyr D-Val, and D-Leu
- D-Thr D-Val These peptides have unexpectedly been found to have a biological activity to reduce serum triglycerides. Among them, the peptides of D-Pro D-Tyr D-Val and D-Leu D-Thr D-Val substantially exceed the activity of the corresponding natural oligopeptide. Unlike the natural oligopeptides, the peptides obtained from the retro-inverso chemical synthesis process are also available for functional group modifications, if required. This modification further allows for greater specificity and selectivity, and will also permit to tailor the activities of the peptides to suit the patient based on his/her intake of fat composition.
- the peptide may, within the scope of the claimed invention, have minor modifications of a nature that is compatible with biological systems, suitably including phosphorylation, sulphonation or iodination of the D-Tyr and / or D-Thr.
- the D-Pro may, for example, be hydroxylated.
- Widely used automatic solid-phase peptide synthetic methods for performing the modification include N-alpha-acetylation or N-alpha-formylation for eliminating the positive charge of the N-terminus.
- a C-terminal carboxamide or alcohol ester can be readily generated by adopting standard solid-phase peptide synthetic resins.
- the peptide may be modified at the N or C, and suitably both, terminals of the peptide.
- N-terminal NH 2 group is suitably replaced with a COOH group and the C-terminal COOH group is suitably replaced with an NH 2 group.
- This modification may suitably be undertaken using one of the conventional techniques for this purpose.
- a route for this modification involves:
- the pharmaceutical composition is suitably provided in a form selected from the group consisting of a tablet, a powder, a granule, a pill and an injectable form. If provided in an injectable form it is suitably selected from the group consisting of a solution, a suspension and an emulsion.
- the said injectable form may be administered by intravenous, intramuscular, subcutaneous, intracutaneous and intraperitoneal administration.
- the pharmaceutical composition suitably comprises from 1 to 100 mg of said peptide.
- a food composition for administration to a human or an animal comprising a peptide consisting of D-Pro D-Tyr D-Val D-Val, D-Pro D-Tyr D-Val, and D-Leu D-Thr D-Val as an active component.
- Example 1 Chemical Synthesis and Purification of Peptides Peptides of D-Pro D-Tyr D-Val D-Val, D-Pro D-Tyr D-Val and D-Leu D-Thr D-Val were synthesized on an Applied Biosystems/Perkin-Elmer 432A Synergy Peptide Synthesizer using FastMoc cycles. The synthesis chemistry involves
- N- ⁇ -9-fluorenylmethoxycarbonyl (Fmoc) protected D-amino acids N- ⁇ -Fmoc-D-proline, N- ⁇ -Fmoc-O-t-butyl-D-tyrosine, N- ⁇ -Fmoc-D-valine, N- ⁇ -Fmoc-D-leucine, N- ⁇ -Fmoc-O-t-butyl-D-threonine
- N- ⁇ -Fmoc-D-proline N- ⁇ -Fmoc-O-t-butyl-D-tyrosine
- N- ⁇ -Fmoc-D-valine N- ⁇ -Fmoc-D-leucine
- N- ⁇ -Fmoc-O-t-butyl-D-threonine were from NOVABIOCHEM.
- the peptides were cleaved by adding 1.8 ml of trifluoroacetic acid (TFA) with 0.1 ml of 1 ,2-ethanedithiol (EDT) and 0.1 ml of thioanisole as scavengers for 1 hour, then precipitated with 15 ml of methyl tert-butyl ether (MTBE) at 4°C and centrifugation at 2000 xg. The MTBE washing was repeated three more times, and the peptides were solubilized with 20% acetic acid.
- TFA trifluoroacetic acid
- EDT 1 ,2-ethanedithiol
- thioanisole thioanisole
- the MTBE washing was repeated three more times, and the peptides were solubilized with 20% acetic acid.
- Olive oil (250 mg) was administered via gastric intubation to male ICR mice (6-week old, body weight: 20 g), which were fasted overnight.
- the peptides were dissolved in 0.1 ml saline solution and administered orally one hour after lipid administration.
- 0.1 ml of saline solution was administered per mouse.
- blood was collected from the orbital vein under ether anesthesia and the serum was separated by centrifugation (3000 rpm, 30 min, 1°C).
- Serum triglyceride levels were assayed using commercially available methods (e.g. INFINITY (Registered Trade Mark) triglycerides reagent; Sigma Chemical Co.). The results were compared with
- C-NH 2 means that the C-terminal of a peptide has a carboxamide form.
- SEQ ID NO. 2 and SEQ ID NO. 3 display higher activities in lowering elevated serum triglyceride levels than Reference 2 and 3, respectively.
- SEQ ID NO. 1 although less active than Reference Peptide 1 , nevertheless exhibits demonstrable serum triglyceride lowering activity, its activity being about half of Reference Peptide 1.
- the retro-inverso peptides suitably have modified N and C terminals, where the N-terminal of the retro-inverso peptide is converted to replace the NH 2 group with a COOH group and the C-terminal COOH group is replaced with an NH 2 group.
- This modification may be achieved by carrying out a C-2 substituted malonyl (or malonamyl) residue substitution for the N- terminal retro-inverso peptide residue (Residue Ri in Fig. 1 ), and a gem-diamino alkyl residue substitution for the C-terminal retro-inverso peptide residue (Residue R ).
- Figure 1 shows the structural differences between the retro-inverso peptide H- D -R1- D -R2-D-R 3 -D-R 4 -OH (Structure 1 ) and the end-group modified peptide HO-/77R D -R 2 - D -R 3 -gR4-H (Structure II, where m and g denote malonyl and gem-diaminoalkyl residues, respectively).
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2003228114A AU2003228114A1 (en) | 2002-05-23 | 2003-05-23 | A pharmaceutical composition comprising a retro-iverso isomer peptide |
DE60308710T DE60308710T2 (en) | 2002-05-23 | 2003-05-23 | PHARMACEUTICAL COMPOSITION COMPRISING A RETRO-INVERSO ISOMERPEPTIDE |
US10/517,355 US7314867B2 (en) | 2002-05-23 | 2003-05-23 | Pharmaceutical composition comprising a retro-iverso isomer peptide |
EP03725841A EP1549334B1 (en) | 2002-05-23 | 2003-05-23 | Pharmaceutical composition comprising a retro-inverso isomer peptide |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0211849.5A GB0211849D0 (en) | 2002-05-23 | 2002-05-23 | Improvments to retro-inverso isomers |
GB0211849.5 | 2002-05-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003099315A1 true WO2003099315A1 (en) | 2003-12-04 |
WO2003099315A8 WO2003099315A8 (en) | 2005-03-03 |
Family
ID=9937245
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2003/001017 WO2003099315A1 (en) | 2002-05-23 | 2003-05-23 | A pharmaceutical composition comprising a retro-iverso isomer peptide |
Country Status (8)
Country | Link |
---|---|
US (1) | US7314867B2 (en) |
EP (1) | EP1549334B1 (en) |
KR (1) | KR101019246B1 (en) |
AT (1) | ATE340585T1 (en) |
AU (1) | AU2003228114A1 (en) |
DE (1) | DE60308710T2 (en) |
GB (2) | GB0211849D0 (en) |
WO (1) | WO2003099315A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2085120A1 (en) * | 2008-02-01 | 2009-08-05 | Merz Pharma GmbH & Co. KGaA | The use of substances for the treatment of central or peripheral insulin receptor impairment and insulin resistance |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989006970A1 (en) * | 1988-02-02 | 1989-08-10 | Hankyu-Kyoei Bussan Co., Ltd. | Lipid metabolism improving agent and method of its use |
WO1997000890A1 (en) * | 1995-06-23 | 1997-01-09 | Hankyu-Kyoei Bussan Co., Ltd. | Peptide that inhibits blood triglyceride level rise and blood triglyceride level rise inhibitor containing said peptide as active ingredient |
EP0838473A1 (en) * | 1996-03-22 | 1998-04-29 | Hankyu Kyoei Bussan Co., Ltd. | Peptide for inhibiting blood triglyceride level rise and inhibitor for blood triglyceride level rise comprising the peptide as active ingredient |
US5756467A (en) * | 1993-03-24 | 1998-05-26 | Itoham Foods Inc. | Adipocyte differentiation inhibiting peptide and adipocyte differentiation inhibiting agent using the peptide as active component thereof |
JPH11263733A (en) * | 1998-03-17 | 1999-09-28 | Hankyu Kyoei Bussan Inc | Lipid metabolism improver |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4473555A (en) * | 1983-10-17 | 1984-09-25 | Syntex (U.S.A.) Inc. | Nona- and dodecapeptides for augmenting natural killer cell activity |
EP0253190B1 (en) | 1986-07-16 | 1992-12-30 | ENIRICERCHE S.p.A. | Partially retro-inverted tuftsin analogues, method for the preparation thereof and pharmaceutical compositions containing them |
US5723443A (en) * | 1988-02-02 | 1998-03-03 | Hankyu-Kyoei Bussan Co. Ltd. | Lipid metabolism promoting agent and its use |
US5218089A (en) * | 1988-12-23 | 1993-06-08 | Sclavo S.P.A. | Retro-inverso analogues of thymopentin and the method for their synthesis |
CA2092541A1 (en) * | 1990-09-27 | 1992-03-28 | Gail F. Seelig | Antagonists of human gamma interferon |
US6046168A (en) * | 1993-03-24 | 2000-04-04 | Hankyu-Kyoei Bussan Co., Ltd. | Peptide inhibits blood triglyceride level |
JP2800877B2 (en) * | 1993-12-28 | 1998-09-21 | 伊藤ハム株式会社 | Peptide for increasing blood triglyceride concentration and blood triglyceride concentration increase inhibitor containing the peptide as an active ingredient |
US5831003A (en) * | 1996-06-28 | 1998-11-03 | Bayer Corporation | Peptides which bind to prothrombin and thrombin |
US7208572B2 (en) * | 1998-08-21 | 2007-04-24 | Albany Medical College | Leptin-related peptides |
-
2002
- 2002-05-23 GB GBGB0211849.5A patent/GB0211849D0/en not_active Ceased
-
2003
- 2003-05-22 KR KR1020030032468A patent/KR101019246B1/en active IP Right Grant
- 2003-05-23 DE DE60308710T patent/DE60308710T2/en not_active Expired - Fee Related
- 2003-05-23 AT AT03725841T patent/ATE340585T1/en not_active IP Right Cessation
- 2003-05-23 US US10/517,355 patent/US7314867B2/en not_active Expired - Fee Related
- 2003-05-23 WO PCT/KR2003/001017 patent/WO2003099315A1/en active IP Right Grant
- 2003-05-23 AU AU2003228114A patent/AU2003228114A1/en not_active Abandoned
- 2003-05-23 GB GB0311938A patent/GB2389043B/en not_active Expired - Lifetime
- 2003-05-23 EP EP03725841A patent/EP1549334B1/en not_active Expired - Lifetime
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989006970A1 (en) * | 1988-02-02 | 1989-08-10 | Hankyu-Kyoei Bussan Co., Ltd. | Lipid metabolism improving agent and method of its use |
US5756467A (en) * | 1993-03-24 | 1998-05-26 | Itoham Foods Inc. | Adipocyte differentiation inhibiting peptide and adipocyte differentiation inhibiting agent using the peptide as active component thereof |
WO1997000890A1 (en) * | 1995-06-23 | 1997-01-09 | Hankyu-Kyoei Bussan Co., Ltd. | Peptide that inhibits blood triglyceride level rise and blood triglyceride level rise inhibitor containing said peptide as active ingredient |
EP0838473A1 (en) * | 1996-03-22 | 1998-04-29 | Hankyu Kyoei Bussan Co., Ltd. | Peptide for inhibiting blood triglyceride level rise and inhibitor for blood triglyceride level rise comprising the peptide as active ingredient |
JPH11263733A (en) * | 1998-03-17 | 1999-09-28 | Hankyu Kyoei Bussan Inc | Lipid metabolism improver |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2085120A1 (en) * | 2008-02-01 | 2009-08-05 | Merz Pharma GmbH & Co. KGaA | The use of substances for the treatment of central or peripheral insulin receptor impairment and insulin resistance |
WO2009095265A1 (en) * | 2008-02-01 | 2009-08-06 | Merz Pharma Gmbh & Co. Kgaa | The use of substances for the treatment of central or peripheral insulin receptor impairment and insulin resistance |
Also Published As
Publication number | Publication date |
---|---|
AU2003228114A8 (en) | 2003-12-12 |
KR20030091739A (en) | 2003-12-03 |
US7314867B2 (en) | 2008-01-01 |
AU2003228114A1 (en) | 2003-12-12 |
ATE340585T1 (en) | 2006-10-15 |
EP1549334A1 (en) | 2005-07-06 |
WO2003099315A8 (en) | 2005-03-03 |
DE60308710T2 (en) | 2007-09-06 |
KR101019246B1 (en) | 2011-03-04 |
GB0211849D0 (en) | 2002-07-03 |
DE60308710D1 (en) | 2006-11-09 |
EP1549334A4 (en) | 2005-11-09 |
GB0311938D0 (en) | 2003-06-25 |
EP1549334B1 (en) | 2006-09-27 |
GB2389043B (en) | 2005-07-27 |
GB2389043A (en) | 2003-12-03 |
US20050261199A1 (en) | 2005-11-24 |
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