WO1998037100B1 - Therapeutic use of the smr1 protein and active derivatives thereof - Google Patents
Therapeutic use of the smr1 protein and active derivatives thereofInfo
- Publication number
- WO1998037100B1 WO1998037100B1 PCT/EP1998/000956 EP9800956W WO9837100B1 WO 1998037100 B1 WO1998037100 B1 WO 1998037100B1 EP 9800956 W EP9800956 W EP 9800956W WO 9837100 B1 WO9837100 B1 WO 9837100B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- peptide
- xqhnpr
- therapeutic
- smr1
- biologically active
- Prior art date
Links
Abstract
The present invention pertains to the use of a peptide molecule consisting in a maturation product of SMR1 (Submandibular rat protein 1) of structural formula QHNPR, as well as the biologically active derivatives of the said peptide, for preventing or treating diseases associated with a mineral ion imbalance in a human or an animal body. More particularly, the present invention relates to the therapeutic use of the above-cited molecules for preventing or treating an hydromineral imbalance in organs and tissues such as kidney, bone, dental enamel, dental ivory, gut matrix, pancreas or glandular gastric mucosa. This invention also deals with therapeutic compositions comprising a pharmaceutically active amount of the above-described therapeutic molecules as well as with therapeutic methods using the said therapeutic compositions. Finally, the present invention relates to processes for selecting ligand molecules that possess an agonist or an antagonist biological activity on the target receptor of the QHNPR pentapeptide as well as to the selected ligand molecules themselves.
Claims
88
AMENDED CLAIMS
[received by the International Bureau on 19 January 1999 (19 01 99), original claims 1-45 replaced by amended claims 1-50 (9 pages)]
1 A therapeutic method for preventing or treating diseases caused by a metabolic imbalance, such as a mineral ion imbalance in a mammal said method comprising administering to the mammal a composition comprising a pharmaceutically active amount of an SMR1 protein, or a maturation product of the SMR1 protein or of one of its biologically active derivatives 2 A therapeutic method for preventing or treating a disorder affecting the bone in a mammal, said method comprising administering to the mammal a composition comprising a pharmaceutically active amount of an SMR1 protein, or a maturation product of the SMR1 protein or of one of its biologically
active derivatives 3 A therapeutic method according to claim 2 for preventing or treating osteoporosis
4 The therapeutic method according to claim 1 or 2 nerein said mammal is a human
5 The therapeutic method according to claim 1 or 2 wherein the therapeutic composition comprises a peptide of formula XQHNPR, wherein X is a hydrogen atom, an ammo acid V, or a polypeptide VR, VRG, VRGP VRGPR or VRGPRR, or one of its biologically active derivatives
6 The therapeutic method according to claim 5 wherein the peptide
XQHNPR or one of its biologically active derivative peptides comprises one or more ammo acids in the D-form
7 The therapeutic method according to claim 1 or 2 wherein the
89
therapeutic composition is a liquid solution
8 The therapeutic method according to claim 1 or 2 wherein the
therapeutic composition is a gel
9 The therapeutic method according to claim 1 or 2 wherein the
therapeutic composition is a dry powder
10 The therapeutic method according to claim 1 or 2 wherein the
therapeutic composition is a controlled drug delivery device
11 The therapeutic method according to claim 1 or 2 wherein the
therapeutic composition is administered locally near a site to be treated 12 The therapeutic method according to claim 1 or 2 wherein the therapeutic composition is administered by the orally route
13 A method for screening ligand molecules that specifically bind to a target receptor for an XQHNPR peptide, comprising the steps of a) preparing a confluent target cell culture monolayer or preparing a target organ specimen or a tissue sample, b) adding a candidate molecule to be tested in competition with a half-saturating concentration of labeled peptide,
c) incubating the cell culture, organ specimen or tissue sample of
step a) in the presence of the labeled candidate molecule for a time sufficient for specific binding to take place, and
d) quantifying the label specifically bound to the target cell culture, organ specimen or tissue sample
14 A method for determining an affinity of ligand molecules that
specifically bind to a target receptor for a XQHNPR peptide, comprising the steps of
a) preparing a confluent target cell culture monolayer or preparing a
target organ specimen or a tissue sample, b) adding a candidate molecule to be tested that has been previously
labeled with a radioactive or a nonradioactive label, c) incubating the cell culture, organ specimen or tissue sample of step a) in the presence of the labeled candidate molecule for a time sufficient for
specific binding to take place, d) quantifying the label specifically bound to the target cell culture,
organ specimen or tissue sample
15 A method for screening candidate ligand molecules that possess
an agonist or an antagonist biological activity on a target receptor of an XQHNPR peptide, comprising the steps of a) preparing a biological material comprising a confluent target cell culture monolayer, a target organ specimen or a tissue sample in cryosections or slices,
b) incubating the cell culture, organ specimen or tissue sample of step a) in the presence of (i) 10"10 - 10'5 M of a candidate molecule and (n) a
submaximal concentration of QHNPR for a time sufficient for an adeπylate cyclase activation to take place, and
c) quantifying adenylate cyclase activity present in the biological material of step a), respectively in the presence or in the absence of the candidate
ligand molecule and in the presence or in the absence of a submaximal concentration of QHNPR
16 A biologically active derivative of the XQHNPR polypeptide which has been obtained according to the method of claim 15, provided that said biologically active derivative does not have the following structure Y-HNP-Z,
91
wherein Y denotes a glutamme (Q), a pyroglutamic acid residue, or a sequence of two aminoacids arginine-glutamine (RQ) and Z represents an OH group or a basic
ammo acid, the basic ammo acid being a Lysme (K) or an Argmine (R) or said biologically active derivative does not have the sequence QHNLR or
RQHNLR
17 A method for determining the amount of XQHNPR or one of its biologically active derivatives to be administered to a patient suffering from a metabolic imbalance such as a mineral ion imbalance, comprising the steps of a) incubating a labeled XQHNPR peptide with a polyclonal or a
monoclonal antibody directed against the same peptide, b) bringing into contact immune complexes formed with a biological sample from a patient to be tested suspected to contain an endogenous non-labeled XQHNPR peptide, c) detecting monoclonal or polyclonal antibody-bound labeled peptides that have not been displaced by the endogenous non-labelled XQHNPR
peptide contained in the biological sample in order to determine a concentration of said endogenous peptide that is contained in the biological sample,
d) comparing the concentration of the XQHNPR peptide formed at step c) with the concentration of the XQHNPR peptide normally found in a healthy individual, and
e) calculating the amount of a therapeutic composition, comprising a pharmaceutically active amount of an SMR1 protein, or a maturation product of the
SMR1 protein or of one of its biologically active derivatives, necessary in order to supply the defect of the XQHNPR peptide in body fluids and tissues
18 The method according to claim 17 wherein said XQHNPR
peptide is QHNPR
19 A composition comprising a pharmaceutically effective amount of
- an SMR1 protein,
- an SMR1 maturation product, or - a biologicaly active derivative of the above, in combination with a pharmaceutically effective amount of a molecule involved in regulation of metabolic balance, such as a mineral ion balance, in the
body
20 The composition according to Claim 19 wherein said SMR1
maturation product is an XQHNPR peptide
21 The composition according to Claim 20, wherein said XQHNPR
peptide is a QHNPR pentapeptide or a polymer thereof
22 The therapeutic composition according to claim 19 wherein the
molecule involved in the regulation of the mineral ion balance in the body is parathyroid hormone (PTH)
23 A composition according to claim 19 wherein the molecule involved in the regulation of the mineral ion balance in the body is calcitonm (CT)
24 A therapeutic composition according to claim 19, wherein the molecule involved in the regulation of the mineral ion balance in the body is 1 ,25-dιhydroxyvιtamιn D
25 A method for producing an SMR1 protein maturation product which comprises the steps of
a) optionally amplifying a nucleic acid coding for a desired polypeptide using a pair of primers specific for an SMR1 genomic or cDNA sequence,
b) inserting a nucleic acid coding for SMR1 protein inserted in an
93
appropriate vector, c) inserting a nucleic acid coding for furin in a suitable vector, said vector being the vector of step b) or said vector being a vector different form the
vector of step b) d) culturing, in an appropriate culture medium devoid of serum, a cell host previously transformed or transfected with the recombmant vector of step b)
and c), e) harvesting the culture medium and the cell host, f) separating or purifying, from said culture medium or from a pellet of a
resultant host cell lysate, the thus produced polypeptide of interest, g) characterizing the produced polypeptide of interest, and h) optionally assaying for specific recognition of said peptide by a polyclonal or a monoclonal antibody directed against a WQHNPR peptide
26 The method according to claim 25, wherein said SMR1 protein maturation product is an XQHNPR peptide
27 The method according to claim 25, wherein said amplifying step a) is carried out by SDA, TAS, 3SR NASBA, TMA, LCR, RCR, CPR, Q-beta replicase or PCR
28 The method according to claim 25, wherein the harvesting step e) is carried out by lysing the cell host by sonication or by an osmotic shock
29 The method according to claim 25 wherein the WQHNPR peptide is a QHNPR peptide
30 A method for screening candidate ligand molecules that possess
an agonist or an antagonist biological activity on a target receptor of an XQHNPR peptide, comprising the steps of
ARTICLE 191
a) culturing a eukaryotic cell capable of synthesizing collagen b) incubating the eukaryotic cell of step a) in beta-glycerophosphate in the presence of 1010 - 10'5 M of the candidate molecule and in the presence of a
submaximal concentration of QHNPR peptide, c) quantifying production of a specific metabolite in the presence or in
the absence of the candidate ligand molecule and in the presence or in the absence
of a submaximal concentration of QHNPR
31 The method according to claim 30, wherein said specific
metabolite is calcium, alkaline phosphatase or DNA synthesis 32 A method for screening a candidate ligand molecule that possesses an agonist or an antagonist biological activity on a target receptor of an
XQHNPR pentapeptide, comprising the steps of a) preparing a confluent target cell culture monolayer or preparing a target organ specimen or a tissue sample in cryosections or slices, b) incubating the cell culture, organ specimen or tissue sample of step a) in the presence of 10"10 - 10"5 M of the candidate molecule and in the presence of a submaximal concentration of QHNPR,
d) quantifying production of a corresponding metabolite, respectively in the presence or in the absence of the candidate ligand molecule and in the presence or in the absence of a submaximal concentration of QHNPR
33 The use of an SMR1 protein, or a maturation product of the SMR1 protein or of one of its biologically active derivatives for the preparation of a
medicament for preventing or treating diseases caused by a metabolic imbalance, such as a mineral ion imbalance in a mammal
34 The use of an SMR1 protein, or a maturation product of the SMR1
protein or of one of its biologically active derivatives for the preparation of a medicament for preventing or treating a disorder affecting the bone in a mammal
35 The use according to claim 34 for preventing or treating
osteoporosis. 36 The use according to claim 33 or 34 wherein said mammal is a
human.
37 The use according to claim 33 or 34, wherein the medicament
comprises a peptide of formula XQHNPR, wherein X is a hydrogen atom, an ammo acid V, or a polypeptide VR, VRG, VRGP, VRGPR or VRGPRR, or one of its biologically active derivatives.
38 The use according to claim 37 wherein the peptide XQHNPR or one of its biologically active derivative peptides comprises one or more ammo acids
in the D-form
39 The use according to claim 31 or 34 wherein the medicament is a
liquid solution
40 The use according to claim 33 or 34 wherein the medicament is a gel.
41. The use according to claim 33 or 34 wherein the medicament is a dry powder.
42. The use according to claim 33 or 34 wherein the medicament is a controlled drug delivery device.
43. The use according to claim 33 or 34 wherein the medicament is administered locally near a site to be treated.
44. The use according to claim 33 or 34 wherein the medicament is administered by the orally route.
45. A tissuiar receptor complex for the SMR1-pentapeptide of
sequence QHNPR.
46. A tissuiar receptor complex according to claim 45 with a pHi of 5.58/5.64 ± 0.30, mainly present in the medulla of kidney, and pancreas and in
lesser extent in the bone trabecular matrix.
47. A tissuiar receptor complex according to claim 45 with a pHi of 6.62
± 0.35 mainly present in the glandular gastric mucosa.
48. The use of the tissuiar receptor according to claims 45 to 47 for
screening ligands having an affinity for said receptor. 49. The use of the tissuiar receptor according to claim 48 comprising the steps of :
- contacting said tissuiar receptor with a potential ligand under conditions allowing the binding of said potential ligand by said tissuiar receptor; and
- detecting the complex formed thereby. 50. The use of an SMR1 protein or a maturation product of the SMR1 protein or one of its biologically active derivatives for the preparation of a medicament active on renal tubular reabsorption through the complex described in claim 45.
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/367,703 US6818405B2 (en) | 1997-02-20 | 1998-02-19 | Therapeutic use of the SMR1 protein and active derivatives thereof |
AU67219/98A AU6721998A (en) | 1997-02-20 | 1998-02-19 | Therapeutic use of the smr1 protein and active derivatives thereof |
EP98912339A EP1007566B1 (en) | 1997-02-20 | 1998-02-19 | Therapeutic use of the smr1 protein and active derivatives thereof |
DE69835680T DE69835680T2 (en) | 1997-02-20 | 1998-02-19 | THERAPEUTIC USE OF SMR1 PROTEIN AND ITS ACTIVE DERIVATIVES |
CA002281912A CA2281912A1 (en) | 1997-02-20 | 1998-02-19 | Therapeutic use of the smr1 protein and active derivatives thereof |
US10/620,462 US7429448B2 (en) | 1997-02-20 | 2003-07-17 | Therapeutic use of the SMR1 protein and active derivatives thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/801,405 US6589750B2 (en) | 1997-02-20 | 1997-02-20 | Therapeutic use of the SMR1 protein, the SMR1 maturation products, specifically the QHNPR pentapeptide as well as its biologically active derivatives |
US08/801,405 | 1997-02-20 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09367703 A-371-Of-International | 1998-02-19 | ||
US09/367,703 A-371-Of-International US6818405B2 (en) | 1997-02-20 | 1998-02-19 | Therapeutic use of the SMR1 protein and active derivatives thereof |
US10/620,462 Division US7429448B2 (en) | 1997-02-20 | 2003-07-17 | Therapeutic use of the SMR1 protein and active derivatives thereof |
Publications (3)
Publication Number | Publication Date |
---|---|
WO1998037100A2 WO1998037100A2 (en) | 1998-08-27 |
WO1998037100A3 WO1998037100A3 (en) | 1999-01-07 |
WO1998037100B1 true WO1998037100B1 (en) | 1999-03-04 |
Family
ID=25181003
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1998/000956 WO1998037100A2 (en) | 1997-02-20 | 1998-02-19 | Therapeutic use of the smr1 protein and active derivatives thereof |
Country Status (10)
Country | Link |
---|---|
US (4) | US6589750B2 (en) |
EP (2) | EP1007566B1 (en) |
AT (1) | ATE337339T1 (en) |
AU (1) | AU6721998A (en) |
CA (1) | CA2281912A1 (en) |
DE (1) | DE69835680T2 (en) |
DK (1) | DK1007566T3 (en) |
ES (1) | ES2271991T3 (en) |
PT (1) | PT1007566E (en) |
WO (1) | WO1998037100A2 (en) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6589750B2 (en) | 1997-02-20 | 2003-07-08 | Institut Pasteur | Therapeutic use of the SMR1 protein, the SMR1 maturation products, specifically the QHNPR pentapeptide as well as its biologically active derivatives |
DK1593387T3 (en) * | 1999-06-23 | 2009-03-02 | Pasteur Institut | Compositions for the treatment of uninhibited interpersonal and behavioral disorders |
PT1216707E (en) | 2000-12-22 | 2005-06-30 | Pasteur Institut | NEW THERAPEUTIC UTILIZATIONS FOR A SMR-1-PEPTIDEO |
SI2246360T1 (en) | 2003-01-28 | 2012-10-30 | Ironwood Pharmaceuticals Inc | Compositions for the treatment of gastrointestinal disorders |
US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
ES2390075T3 (en) * | 2004-03-19 | 2012-11-06 | Institut Pasteur | Peptides derived from the human BPLP protein, polynucleotides encoding said peptides and antibodies directed against said peptides |
DE102004026744A1 (en) * | 2004-05-28 | 2005-12-29 | Philipps-Universität Marburg | Invention relating to cDNA production from cells after laser microdissection |
US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
ES2559319T3 (en) | 2007-06-04 | 2016-02-11 | Synergy Pharmaceuticals Inc. | Guanylate cliclas agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
PT2274321T (en) * | 2008-04-07 | 2019-03-21 | Pasteur Institut | Opiorphin peptide derivatives as potent inhibitors of enkephalin - degrading ectopetidases |
FR2931362B1 (en) | 2008-05-26 | 2017-08-18 | Pasteur Institut | OPIORPHINE FOR USE AS A PSYCHOSTIMULANT. |
EP2810951B1 (en) | 2008-06-04 | 2017-03-15 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
ES2624828T3 (en) | 2008-07-16 | 2017-07-17 | Synergy Pharmaceuticals Inc. | Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and others |
CA2745694C (en) | 2008-12-03 | 2018-03-27 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase c agonists and methods of use |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
EP3366698A1 (en) | 2011-03-01 | 2018-08-29 | Synergy Pharmaceuticals Inc. | Guanylate cyclase c agonists |
AU2014235215A1 (en) | 2013-03-15 | 2015-10-01 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
JP2016514670A (en) | 2013-03-15 | 2016-05-23 | シナジー ファーマシューティカルズ インコーポレイテッド | Guanylate cyclase receptor agonists in combination with other drugs |
HRP20240805T1 (en) | 2013-06-05 | 2024-09-27 | Bausch Health Ireland Limited | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
CN109212006A (en) * | 2018-08-24 | 2019-01-15 | 北京艾普希隆生物科技有限公司 | A kind of unicellular agarose gel electrophoresis kit |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1983003972A1 (en) | 1982-05-06 | 1983-11-24 | Massachusetts Institute Of Technology | Production of enterovirus neutralizing antibodies from vp1 |
US4699877A (en) | 1982-11-04 | 1987-10-13 | The Regents Of The University Of California | Methods and compositions for detecting human tumors |
GB8327966D0 (en) | 1983-10-19 | 1983-11-23 | Nyegaard & Co As | Chemical compounds |
IL78444A (en) * | 1986-04-08 | 1992-05-25 | Yeda Res & Dev | Human gamma interferon-specific receptor protein,antibody against said protein,and compositions containing said protein and antibody |
FR2637600B1 (en) * | 1988-10-11 | 1992-03-06 | Pasteur Institut | PEPTIDES AND POLYPEPTIDES FROM THE RAT SUB-MAXILLARY GLAND, CORRESPONDING MONOCLONAL AND POLYCLONAL ANTIBODIES, HYBRIDOMAS AND APPLICATIONS THEREOF FOR DIAGNOSIS, DETECTION OR THERAPEUTIC PURPOSES |
US5219548A (en) * | 1990-10-01 | 1993-06-15 | Board Of Regents, The University Of Texas System | High affinity halogenated-tamoxifen derivatives and uses thereof |
WO1995000848A1 (en) * | 1993-06-23 | 1995-01-05 | The Regents Of The University Of California | Compositions and methods for anti-addictive narcotic analgesis acivity screening and treatments |
US6589750B2 (en) * | 1997-02-20 | 2003-07-08 | Institut Pasteur | Therapeutic use of the SMR1 protein, the SMR1 maturation products, specifically the QHNPR pentapeptide as well as its biologically active derivatives |
DK1593387T3 (en) * | 1999-06-23 | 2009-03-02 | Pasteur Institut | Compositions for the treatment of uninhibited interpersonal and behavioral disorders |
PT1216707E (en) * | 2000-12-22 | 2005-06-30 | Pasteur Institut | NEW THERAPEUTIC UTILIZATIONS FOR A SMR-1-PEPTIDEO |
-
1997
- 1997-02-20 US US08/801,405 patent/US6589750B2/en not_active Expired - Lifetime
-
1998
- 1998-02-19 EP EP98912339A patent/EP1007566B1/en not_active Expired - Lifetime
- 1998-02-19 AT AT98912339T patent/ATE337339T1/en active
- 1998-02-19 ES ES98912339T patent/ES2271991T3/en not_active Expired - Lifetime
- 1998-02-19 AU AU67219/98A patent/AU6721998A/en not_active Abandoned
- 1998-02-19 DE DE69835680T patent/DE69835680T2/en not_active Expired - Lifetime
- 1998-02-19 DK DK98912339T patent/DK1007566T3/en active
- 1998-02-19 EP EP06009596A patent/EP1702929A3/en not_active Withdrawn
- 1998-02-19 WO PCT/EP1998/000956 patent/WO1998037100A2/en active IP Right Grant
- 1998-02-19 PT PT98912339T patent/PT1007566E/en unknown
- 1998-02-19 CA CA002281912A patent/CA2281912A1/en not_active Abandoned
- 1998-02-19 US US09/367,703 patent/US6818405B2/en not_active Expired - Fee Related
-
2003
- 2003-05-12 US US10/435,564 patent/US20030195155A1/en not_active Abandoned
- 2003-07-17 US US10/620,462 patent/US7429448B2/en not_active Expired - Fee Related
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