WO1997027203B1 - Bis-maleimido cross-linking agents - Google Patents
Bis-maleimido cross-linking agentsInfo
- Publication number
- WO1997027203B1 WO1997027203B1 PCT/US1997/001130 US9701130W WO9727203B1 WO 1997027203 B1 WO1997027203 B1 WO 1997027203B1 US 9701130 W US9701130 W US 9701130W WO 9727203 B1 WO9727203 B1 WO 9727203B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cross
- enzyme
- linking agent
- cleavable moiety
- enzymatically cleavable
- Prior art date
Links
- 239000003431 cross linking reagent Substances 0.000 title claims abstract 11
- 102000004190 Enzymes Human genes 0.000 claims abstract 12
- 108090000790 Enzymes Proteins 0.000 claims abstract 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract 4
- 102000005936 beta-Galactosidase Human genes 0.000 claims abstract 3
- 108010005774 beta-Galactosidase Proteins 0.000 claims abstract 3
- 102000004169 proteins and genes Human genes 0.000 claims 4
- 108090000623 proteins and genes Proteins 0.000 claims 4
- GZCGUPFRVQAUEE-KCDKBNATSA-N D-(+)-Galactose Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-KCDKBNATSA-N 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical group [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M butyrate Chemical group CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 claims 2
- 150000002338 glycosides Chemical group 0.000 claims 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 239000010452 phosphate Chemical group 0.000 claims 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N Succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims 1
- -1 acetal glycoside Chemical class 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 claims 1
- 239000008103 glucose Substances 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M isothiocyanate Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims 1
- 229910052757 nitrogen Chemical group 0.000 claims 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229960002317 succinimide Drugs 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000011593 sulfur Chemical group 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N α-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 abstract 3
- 238000004166 bioassay Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 229920001184 polypeptide Polymers 0.000 abstract 1
Abstract
Formation of an intramolecular cross-link in enzyme donor polypeptide fragments of β-galactosidase, thereby forming a cyclic enzyme donor which is hindered from complementation with an enzyme acceptor fragment to form active of β-galactosidase. The cyclic enzyme donor can be linearized by cleaving to restore complementation ability. Assays in which such cyclic enzyme donors are linearized by specific analytes are disclosed, as well as novel homobifunctional bi-maleimido cross-linking agents of formula (I), wherein R is hydroxy or acetate.
Claims
1. A cross-linking agent of the formula W-(CH2)„-X-CH(OY)-(CH2)„-Z wherein: W and Z are each a functional group selected from the group consisting of maleimide, succinimide and thiocyanate; n is a number from 1 to 10;
X is oxygen, sulfur or nitrogen; and
Y is an enzymatically cleavable moiety selected from the group consisting of glycosides, phosphate, butyrate and acetate.
2. The cross-linking agent of claim 1 , wherein the enzymatically cleavable moiety is a glycoside.
3. The cross-linking agent of claim 2, wherein the enzymatically cleavable moiety is an acetal glycoside.
4. The cross-linking agent of claim 2, wherein the enzymatically cleavable moiety is selected from the group consisting of galactose, mannose, and glucose.
5. The cross-linking agent of claim 1, wherein the enzymatically cleavable moiety is selected from the group consisting of phosphate, butyrate and acetate.
6. The cross-linking agent of any of the preceding claims, wherein W and Z are maleimide and Y is galactose.
-29-
7. A cross-linking agent of the formula
8. The compound l,7-bismaleimido-4-O-(tetraacetyl-β-D-galactopyranosyl)-5- oxaheptane.
9. The compound l,7-bismaleimido-4-O-(β-D-galactopyranosyl)-5-oxaheptane.
10. A method for forming a cross-linked protein, comprising contacting the protein with the cross-linking agent of any of claims 1-9.
11. The method of claim 10, wherein the protein is a portion of an enzyme.
12. The method of claim 11 , wherein the protein is an enzyme donor of β-galactosidase.
13. An enzyme portion cross-linked using the cross-linking agent of any of claims 1-9.
14. A method of determining the presence or amount of an enzyme in a sample, comprising contacting any enzyme in the sample with an enzyme portion that has been cross-linked using the agent of any of claims 1-9, wherein the enzymatically cleavable moiety of the agent is cleavable by the enzyme to be determined.
-30- AMENDED SHEET (ARTICLE 1B>
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE69709448T DE69709448T2 (en) | 1996-01-26 | 1997-01-23 | Bismaleimide LINKER |
| EP97903949A EP0817789B1 (en) | 1996-01-26 | 1997-01-23 | Bis-maleimido cross-linking agents |
| AT97903949T ATE211480T1 (en) | 1996-01-26 | 1997-01-23 | BISMALEIC ACID IMIDE CROSSLINKER |
| AU18378/97A AU1837897A (en) | 1996-01-26 | 1997-01-23 | Bis-maleimido cross-linking agents |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US59201596A | 1996-01-26 | 1996-01-26 | |
| US08/592,015 | 1996-01-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1997027203A1 WO1997027203A1 (en) | 1997-07-31 |
| WO1997027203B1 true WO1997027203B1 (en) | 1997-09-12 |
Family
ID=24368925
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1997/001130 WO1997027203A1 (en) | 1996-01-26 | 1997-01-23 | Bis-maleimido cross-linking agents |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US5976783A (en) |
| EP (1) | EP0817789B1 (en) |
| JP (1) | JP2863638B2 (en) |
| AT (1) | ATE211480T1 (en) |
| AU (1) | AU1837897A (en) |
| DE (1) | DE69709448T2 (en) |
| ES (1) | ES2170937T3 (en) |
| WO (1) | WO1997027203A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999006072A1 (en) * | 1997-07-30 | 1999-02-11 | Boehringer Mannheim Corporation | Cyclized prodrugs |
| GB0125658D0 (en) * | 2001-10-25 | 2001-12-19 | Ssl Int Plc | Medicaments |
| US7993749B2 (en) * | 2005-12-16 | 2011-08-09 | University Of Kansas | Nanoparticles comprising a nanoparticle template and a polymer shell having an amide side chain, and method of making thereof |
| US20130041134A1 (en) * | 2009-11-05 | 2013-02-14 | Sangart ,Inc. | Methods for preparing polyethylene glycol maleimide using n-(2-hydroxyethyl) maleimide as a starting material |
| JP6590474B2 (en) * | 2014-09-25 | 2019-10-16 | 国立大学法人埼玉大学 | Method for producing chemically cross-linked peptide, chemically cross-linked peptide produced using the method, and peptide library by cDNA display method constructed using the peptide |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4179337A (en) * | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
| US4671958A (en) * | 1982-03-09 | 1987-06-09 | Cytogen Corporation | Antibody conjugates for the delivery of compounds to target sites |
| US4493795A (en) * | 1983-10-17 | 1985-01-15 | Syntex (U.S.A.) Inc. | Synthetic peptide sequences useful in biological and pharmaceutical applications and methods of manufacture |
| US4708929A (en) * | 1984-10-29 | 1987-11-24 | Microgenics Corporation | Methods for protein binding enzyme complementation assays |
| WO1986002666A1 (en) * | 1984-10-29 | 1986-05-09 | Microgenics Corporation | Methods for protein binding enzyme complementation assays |
| US4766106A (en) * | 1985-06-26 | 1988-08-23 | Cetus Corporation | Solubilization of proteins for pharmaceutical compositions using polymer conjugation |
| AU626809B2 (en) * | 1987-10-30 | 1992-08-13 | Abbott Laboratories | Heterobifunctional coupling agents |
| EP0321973B1 (en) * | 1987-12-23 | 1993-11-03 | BOEHRINGER INGELHEIM INTERNATIONAL GmbH | Expression of the virally encoded protease P2A of HRV2 |
| JPH04504713A (en) * | 1988-11-18 | 1992-08-20 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | Conjugated polypeptides and methods for their preparation and use |
| US5166322A (en) * | 1989-04-21 | 1992-11-24 | Genetics Institute | Cysteine added variants of interleukin-3 and chemical modifications thereof |
| CA1335707C (en) * | 1989-08-15 | 1995-05-30 | Pyare Khanna | Drug screening assay |
| EP0419081A3 (en) * | 1989-09-22 | 1992-07-22 | Microgenics Corporation | Method for protein binding enzyme complementation assays |
| US5164300A (en) * | 1989-12-28 | 1992-11-17 | Washington University | Method for determining activity of retroviral protease |
| US5011910A (en) * | 1989-12-28 | 1991-04-30 | Washington University | Reagent and method for determining activity of retroviral protease |
| WO1992003559A2 (en) * | 1990-08-28 | 1992-03-05 | Boehringer Ingelheim International Gmbh | Test system for checking the activity of viral proteinases |
| US5171662A (en) * | 1990-09-13 | 1992-12-15 | The Upjohn Company | Method of detecting HIV protease activity |
| CA2068190C (en) * | 1991-05-15 | 1996-12-17 | Microgenics Corporation | Methods and compositions for enzyme complementation assays using the omega region of beta-galactosidase |
| CA2075858C (en) * | 1991-08-15 | 1998-05-19 | Scott J. Eisenbeis | Detection of complementary nucleotide sequences |
| US5412083A (en) * | 1992-04-16 | 1995-05-02 | Northeastern University | Carbohydrate heterobifunctional cross-linking reagent |
| DE4310141A1 (en) * | 1993-03-29 | 1994-10-06 | Boehringer Mannheim Gmbh | Homobidental trifunctional linkers |
| US5436131A (en) * | 1993-04-02 | 1995-07-25 | Merck & Co., Inc. | Color screening assay for identifying inhibitor resistant HIV protease mutants |
| US5439798A (en) * | 1993-12-17 | 1995-08-08 | Boehringer Mannheim Corporation | Maleimide adduct conjugates of procainamide and NAPA |
| US5506115A (en) * | 1994-04-29 | 1996-04-09 | G. D. Searle & Co. | Reagent and method for determining activity of herpes protease |
| WO1996012492A1 (en) * | 1994-10-25 | 1996-05-02 | Merck & Co., Inc. | Microbial synthesis of hiv protease inhibitors |
| US5861267A (en) * | 1995-05-01 | 1999-01-19 | Vertex Pharmaceuticals Incorporated | Methods, nucleotide sequences and host cells for assaying exogenous and endogenous protease activity |
| AU6754196A (en) * | 1995-08-25 | 1997-03-19 | Rational Drug Design Laboratories | Novel fluorescent substrate for assaying activity of hepatitis c virus ns3 serine protease |
-
1997
- 1997-01-23 EP EP97903949A patent/EP0817789B1/en not_active Expired - Lifetime
- 1997-01-23 JP JP9527023A patent/JP2863638B2/en not_active Expired - Fee Related
- 1997-01-23 WO PCT/US1997/001130 patent/WO1997027203A1/en active IP Right Grant
- 1997-01-23 AU AU18378/97A patent/AU1837897A/en not_active Abandoned
- 1997-01-23 AT AT97903949T patent/ATE211480T1/en active
- 1997-01-23 DE DE69709448T patent/DE69709448T2/en not_active Expired - Fee Related
- 1997-01-23 ES ES97903949T patent/ES2170937T3/en not_active Expired - Lifetime
- 1997-06-26 US US08/883,632 patent/US5976783A/en not_active Expired - Fee Related
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