US20040039167A1 - Maurotoxin, pi1 and hstx1 derivatives - Google Patents
Maurotoxin, pi1 and hstx1 derivatives Download PDFInfo
- Publication number
- US20040039167A1 US20040039167A1 US10/363,622 US36362203A US2004039167A1 US 20040039167 A1 US20040039167 A1 US 20040039167A1 US 36362203 A US36362203 A US 36362203A US 2004039167 A1 US2004039167 A1 US 2004039167A1
- Authority
- US
- United States
- Prior art keywords
- derivative
- residue
- residues
- maurotoxin
- replaced
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
- C07K14/43513—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae
- C07K14/43522—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae from scorpions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the invention relates to derivatives of maurotoxin and of particular toxins belonging to the same structural class of K + channel-acting short-chain scorpion toxins (less than 40 amino acid residues) that are cross-linked by four disulfide bridges, such as Pi1 and HsTx1.
- disulfide bridges such as Pi1 and HsTx1.
- toxin derivatives contemplated by the invention are truncated, modified, and mutated toxins (with either natural or non-natural amino acid residues, or non-natural peptide bonds or linkages) with four, or less than four, disulfide bridges. Mimetics of these compounds are also included.
- the invention also relates to the use of all these derivatives and mimetics for the treatment of neurological disorders, including immunological neurological disorders, associated with their action on modulation or blockade of specific K + channels, Ca 2+ -activated and/or voltage-gated subtypes, and to pharmaceutical compositions containing them.
- Maurotoxin a toxin from the venom of the Tunisian chactidae scorpion Scorpio maurus palmatus, is a 34-mer peptide cross-linked by four disulfide bridges.
- the sequence of amino acid residues in MTX is VSCTGSKDCYAPCRKQTGCPNAKClNKSCKCYGC-NH 2 [SEQ. ID NO. 1].
- MTX belongs to a distinct family of short-chain scorpion toxins with less than 40 residues, that are active onto several potassium channel subtypes (Kv and KCa channels).
- This family can be distinguished by the presence of an additional disulfide bridge (four instead of the three commonly present in such toxins).
- This structural class also includes Pi1 [SEQ. ID NO. 2] and HsTx1 [SEQ. ID NO. 3] from the venoms of the scorpions Pandinus imperator and Heteroticians spinnifer , respectively.
- These toxins share from 53 to 68% sequence identity with MTX but display different pharmacological selectivities. For instance, MTX and Pi1 are both active on some Ca 2+ -activated K + channels, e.g. apamin-sensitive SK channels, whereas HsTx1 is reportedly inactive on these channel types.
- MTX was found to be active on rat Kv1.3 channels contrary to synthetic Pi1.
- MTX structurally differs from Pi1 and HsTx1, but also from other “classical” three disulfide-bridged scorpion toxins, by its unique disulfide bridge pattern.
- the half-cystine pairings are of the type C1-C4, C2-C5 and C3-C6 (e.g. charybdotoxin, PO 5 , agitoxin 2, leiurotoxin 1).
- the invention provides MTX, Pi1 and HsTx1 derivatives, in which specific residue replacements, or a reorganization of half-cystine pairings has taken place, resulting in a novel, highly potent and more selective pharmacological profile.
- the substitution of the MTX half-cystine residues results in a two disulfide-bridged MTX analog, i.e. VSCTGSKDAbuYAPCRKQTGAbuPNAKClNKSAbuKCYGAbu-NH 2 , with novel, non-native arrangement of the half-cystine pairings (Cys3-Cys24 and Cys13-Cys31).
- MTX and Pil derivatives such as [Abu9,19,29,34]-MTX or [Q15]-MTX are neither lethal nor toxic when injected intracerebroventricularly in these mice at active concentrations (up to 1.25 mg/kg in the case of [Abu9, 19, 29, 34]-MTX).
- the MTX derivatives, as well as the MTX structurally homologous Pi1 or HsTx1 derivatives, of the invention are thus of potential therapeutic value for treating mammalian (including human) pathologies that are associated with a dysfunctioning of Ca 2+ -activated and/or voltage-gated Kv channel subtypes.
- pathologies include immune and/or neurological diseases like multiple sclerosis, Parkinson's and Alzheimer's diseases, both thought to be associated with a dysfunctioning of Ca 2+ -activated and/or voltage-gated K + channel subtype(s).
- the axonal impulse propagation ensures a continued transmission of nervous signals to remote targets. In a number of neuropathies, the nervous conduction is either slowed down or locked.
- K + -channel blockers including Ca 2+ -activated K + channel-acting and/or Kv-acting MTX/Pi1/HsTx1-derived peptides such as [Q15]-MTX, Pi1 amidated at C-terminus, [Abu9,19,29,34]-MIX, are of potential therapeutic value as symptomatic therapy of multiple sclerosis and related neuropathies, as well as for use as selective immuno-suppressant drugs by their blocking action on Ca 2+ -activated and/or Kv channels. Further, it can be speculated that such peptide blockers, in the CNS, could enhance transmitter release in pathways affected by progressive neurodegenerative diseases such as Alzheimer's disease.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/009,675 US7829666B2 (en) | 2000-09-04 | 2008-01-22 | Maurotoxin, PI1 and HSTX1 derivatives |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0021639.0 | 2000-09-04 | ||
GB0021639A GB0021639D0 (en) | 2000-09-04 | 2000-09-04 | Maurotoxin derivatives |
GB0024538.1 | 2000-10-06 | ||
GB0024538A GB0024538D0 (en) | 2000-10-06 | 2000-10-06 | Maurotoxin pil and hstx1 derivatives |
PCT/EP2001/010173 WO2002020596A2 (en) | 2000-09-04 | 2001-09-03 | Maurotoxin, pi1 and hstx1 derivatives |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/009,675 Continuation US7829666B2 (en) | 2000-09-04 | 2008-01-22 | Maurotoxin, PI1 and HSTX1 derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040039167A1 true US20040039167A1 (en) | 2004-02-26 |
Family
ID=26244958
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/363,622 Abandoned US20040039167A1 (en) | 2000-09-04 | 2001-09-03 | Maurotoxin, pi1 and hstx1 derivatives |
US12/009,675 Expired - Fee Related US7829666B2 (en) | 2000-09-04 | 2008-01-22 | Maurotoxin, PI1 and HSTX1 derivatives |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/009,675 Expired - Fee Related US7829666B2 (en) | 2000-09-04 | 2008-01-22 | Maurotoxin, PI1 and HSTX1 derivatives |
Country Status (7)
Country | Link |
---|---|
US (2) | US20040039167A1 (de) |
EP (1) | EP1315747B1 (de) |
AT (1) | ATE321778T1 (de) |
AU (1) | AU2002212201A1 (de) |
DE (1) | DE60118418T2 (de) |
ES (1) | ES2261491T3 (de) |
WO (1) | WO2002020596A2 (de) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090118181A1 (en) * | 2007-05-22 | 2009-05-07 | Walker Kenneth W | Compositions and methods for producing bioactive fusion proteins |
US20090281028A1 (en) * | 2006-10-25 | 2009-11-12 | Sullivan John K | OSK1 peptide analogs and pharmaceutical compositions |
US7745575B1 (en) | 2004-06-25 | 2010-06-29 | Cellpep Pharma Inc. | OsK1 derivatives |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE202013104200U1 (de) | 2013-09-13 | 2013-10-10 | Flühs Drehtechnik GmbH | Einhandhebelkartusche |
AU2013404615B2 (en) | 2013-10-28 | 2018-05-17 | Baylor College Of Medicine | Novel scorpion toxin analogue and method for treating autoimmune diseases |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5945329A (en) * | 1993-10-28 | 1999-08-31 | Carlsberg A/S | Customized proteases |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ83294A3 (en) * | 1991-10-12 | 1995-08-16 | Univ California | The use of thioredox proteins for reducing disulfidic bonds |
CA2253937A1 (en) * | 1996-05-10 | 1997-11-20 | Phylomed Corporation | Methods for oxidizing disulfide bonds using ozone |
GB9627115D0 (en) * | 1996-12-31 | 1997-02-19 | Centre Nat Rech Scient | Alpha-amino-butyrate derivatives of venoms |
-
2001
- 2001-09-03 DE DE60118418T patent/DE60118418T2/de not_active Expired - Lifetime
- 2001-09-03 US US10/363,622 patent/US20040039167A1/en not_active Abandoned
- 2001-09-03 AT AT01980332T patent/ATE321778T1/de not_active IP Right Cessation
- 2001-09-03 ES ES01980332T patent/ES2261491T3/es not_active Expired - Lifetime
- 2001-09-03 EP EP01980332A patent/EP1315747B1/de not_active Expired - Lifetime
- 2001-09-03 AU AU2002212201A patent/AU2002212201A1/en not_active Abandoned
- 2001-09-03 WO PCT/EP2001/010173 patent/WO2002020596A2/en active IP Right Grant
-
2008
- 2008-01-22 US US12/009,675 patent/US7829666B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5945329A (en) * | 1993-10-28 | 1999-08-31 | Carlsberg A/S | Customized proteases |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7745575B1 (en) | 2004-06-25 | 2010-06-29 | Cellpep Pharma Inc. | OsK1 derivatives |
US20090281028A1 (en) * | 2006-10-25 | 2009-11-12 | Sullivan John K | OSK1 peptide analogs and pharmaceutical compositions |
US20090299044A1 (en) * | 2006-10-25 | 2009-12-03 | Sullivan John K | DNA encoding chimeric toxin peptide fusion proteins and vectors and mammalian cells for recombinant expression |
US20090305399A1 (en) * | 2006-10-25 | 2009-12-10 | Sullivan John K | DNA encoding OSK1 toxin peptide analogs and vectors and cells for combinant expression |
US7803769B2 (en) | 2006-10-25 | 2010-09-28 | Amgen Inc. | OSK1 peptide analogs and pharmaceutical compositions |
US7820623B2 (en) | 2006-10-25 | 2010-10-26 | Amgen Inc. | Conjugated toxin peptide therapeutic agents |
US7825093B2 (en) | 2006-10-25 | 2010-11-02 | Amgen Inc. | Methods of using OSK1 peptide analogs |
US7834164B2 (en) | 2006-10-25 | 2010-11-16 | Amgen Inc. | DNA encoding OSK1 toxin peptide analogs and vectors and cells for combinant expression |
US7910102B2 (en) | 2006-10-25 | 2011-03-22 | Amgen Inc. | Methods of using conjugated toxin peptide therapeutic agents |
US8043829B2 (en) | 2006-10-25 | 2011-10-25 | Amgen Inc. | DNA encoding chimeric toxin peptide fusion proteins and vectors and mammalian cells for recombinant expression |
US20090118181A1 (en) * | 2007-05-22 | 2009-05-07 | Walker Kenneth W | Compositions and methods for producing bioactive fusion proteins |
US8420779B2 (en) | 2007-05-22 | 2013-04-16 | Amgen Inc. | Compositions and methods for producing bioactive fusion proteins |
Also Published As
Publication number | Publication date |
---|---|
EP1315747B1 (de) | 2006-03-29 |
WO2002020596A3 (en) | 2002-08-01 |
US20090062198A1 (en) | 2009-03-05 |
ATE321778T1 (de) | 2006-04-15 |
WO2002020596A2 (en) | 2002-03-14 |
ES2261491T3 (es) | 2006-11-16 |
AU2002212201A1 (en) | 2002-03-22 |
EP1315747A2 (de) | 2003-06-04 |
DE60118418T2 (de) | 2007-01-11 |
DE60118418D1 (de) | 2006-05-18 |
US7829666B2 (en) | 2010-11-09 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE |
|
AS | Assignment |
Owner name: AMBRILIA BIOPHARMA FRANCE S.A., FRANCE Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SABATIER, JEAN-MARC;MABROUK, KAMEL;ROCHAT, HERVE;REEL/FRAME:020905/0670;SIGNING DATES FROM 20080414 TO 20080422 |
|
AS | Assignment |
Owner name: AMBRILIA BIOPHARMA FRANCE S.A., FRANCE Free format text: CHANGE OF NAME;ASSIGNOR:CELLPEP SA;REEL/FRAME:021120/0616 Effective date: 20060606 |
|
AS | Assignment |
Owner name: CELLPEP PHARMA INC., CANADA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:AMBRILIA BIOPHARMA FRANCE S.A.;REEL/FRAME:021257/0808 Effective date: 20080514 |