EP0675873A1 - Synthese de polymeres codes - Google Patents
Synthese de polymeres codesInfo
- Publication number
- EP0675873A1 EP0675873A1 EP94904077A EP94904077A EP0675873A1 EP 0675873 A1 EP0675873 A1 EP 0675873A1 EP 94904077 A EP94904077 A EP 94904077A EP 94904077 A EP94904077 A EP 94904077A EP 0675873 A1 EP0675873 A1 EP 0675873A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- active
- polymer
- encoding
- carbon atoms
- conjugate
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/0054—Means for coding or tagging the apparatus or the reagents
- B01J2219/00572—Chemical means
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B70/00—Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes
Definitions
- Rational drug design achieves results by intensive analysis of the molecular structure of binding sites, and designing compounds specifically to complement a desired binding site.
- one interested in preparing new antihypertensive compounds might analyze the molecular structure of the ⁇ - adrenergic receptor binding site using X-ray crystallography and/or advanced NMR techniques, and then synthesize compounds calculated to fit within the binding site and complement the charge distribution.
- the other approach is to prepare an enormous library of compounds and select only those compounds which exhibit a desired activity.
- This approach differs from the traditional pharmaceutical cycle of design/synthesize/test/synthesize variants by conducting the screening step in a massively parallel fashion, screening an enormous number of different compounds simultaneously.
- the challenge to this approach is first to provide a group of compounds for screening that is sufficiently numerous and diverse to insure that the activity sought is represented in the group, and second to identify the active compounds at low concentration within the group.
- An important object of the invention is to provide a chemical synthesis method which allows the production of libraries of peptides and/or peptoids along with a unique encoded polymer such as a DNA strand which makes it possible to readily determine the sequence of the peptide or peptoid.
- An advantage of the present invention is that the methodology makes it possible to readily identify and sequence peptides and/or peptoids having desirable biological activities.
- a feature of the present invention is that sequences of peptoids or peptides which contain nonconventional amino acids can still be readily determined by sequencing associated polymers such as DNA sequences which are simultaneously synthesized with the peptoids and encode them.
- the invention provides a rapid method of synthesizing large numbers of conjugates which conjugates are comprised of a peptide/peptoid sequence, e.g., an amino acid sequence associated with a unique encoding sequence, e.g., a DNA sequence.
- the conjugates can be readily synthesized and thereafter screened for biological activity, and when activity is found, the particular peptide/peptoid sequence found to be active can be readily identified by its associated encoding (DNA) strand.
- Each conjugate of the invention is comprised of at least two components with one of the components being the peptide or peptoid sequence which binds to a receptor of interest and the other sequence being a polymer which encodes the binding sequence.
- the invention may utilize standard amino acids and DNA as encoding monomers to produce a chemically diverse library of solution-phase or solid-phase conjugates. In order to further describe the invention in detail, the following definitions are provided.
- nucleic acid and nucleic acid refer to oligomers constructed from DNA and/or RNA bases which may be sequenced using standard DNA sequencing tech ⁇ niques.
- the NAs used herein may include uncommon bases so long as such bases are distinguishable from the other bases employed under the DNA sequencing methods to be used and include peptide-nucleic acids (PNAs) (disclosed by Nielsen, P.E., Egholm, M. , Berg, R.H. & Buchardt, 0. , Science (1991) 254, 1497-1500).
- PNAs peptide-nucleic acids
- Such PNAs could serve as coding strands and the detection would be by hybridi-zation.
- NAs will usually be constructed from monomers linked by phos- phodiester bonds, but other similar linkages may be substituted if desired.
- phosphorothioates may be employed to reduce lability.
- the term "peptide” as used herein refers to the 20 commonly-occurring amino acids: alanine (A) , cysteine (C) , aspartic acid (D) , glutamic acid (E) , phenylalanine (F) , glycine (G) , histidine (H) , isoleucine (I) , lysine (K) , leucine (L) , methionine (M) , asparagine (N) , proline (P) , gluta ine (Q) , arginine (R) , serine (S) , threonine (T) , valine (V) , tryptophan ( ) , and tyrosine (Y) .
- eptoid refers to a non-peptide monomer of the general formula (R) n -X- (L) m , where R is a side chain group, n is at least 1, L is a linking group, m is at least 2, and X is a small organic radical. It is preferred to select L radicals that may be individually protected and deprotected. Preferably n will be 1 or 2 and m will be 2. Monomers wherein m is 3 or greater may be used to form branched active polymers. Presently preferred monomers are N-substituted glycine derivatives of the formula
- R is alkyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms wherein halo is F, Cl, Br, or I, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cyclolkyl of 3-8 carbon atoms, alkoxyalkyl of 2-8 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-12 carbon atoms, arylalkyl of 7-12 carbon atoms substituted with 1-3 radicals independently selected from halo and nitro and hydroxy, aminoalkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, carboxy, carboxyalkyl of 2-6 carbon atoms, carboalkoxy-alkyl of 3-10 carbon atoms, carbamyl, carbamylalkyl of 2-6 carbon atoms, imidazolyl, imid- azolylalkyl of 4-10 carbon atoms
- Active polymers comprise a series of monomers which are linked sequentially.
- the monomers will generally be peptides, peptoids, or carbohydrates in the practice of the instant invention.
- mixture refers to a composition having a plurality of similar components in a single vessel.
- Couple refers to formation of a covalent bond.
- conjugate refers to the combination of any "active polymer” and its associated “coding” polymer.
- the conjugate may be formed using a “coupling moiety” or by binding both the “active polymer” and “encoding polymer” to the same support surface in close proximity with each other so that the two polymers are “associated” with each other.
- both polymers are bound to the same support surface, such as a small bead, the encoding polymer can be readily sequenced off of the bead and the other "active polymers” remaining on the bead will be identified once the encoding sequence is known.
- This invention also describes a methodology to increase the size (>10 8 ) and screening rate of a ligand library.
- the method uses two polymers as above, but specifically utilizes an oligodeoxyribonucleotide for the "coding" strand.
- the use of DNA as the coding strand allows for an increased sensitivity of detection (fmol vs pmol for peptide analysis) .
- This increased sensitivity allows for a larger library size since the amount of polymer needed for detection is reduced dramatically.
- the rate of sequence determination of receptor binders is increased since many samples can be analyzed in parallel.
- the receptor-binding ligand can be identified by bead staining techniques (Lam, K. , Salmon, S., Hersh, E., Hruby, V., Kazmiersky, W. & Knapp, R. , Nature, (1991), 354, 82-84) and the sequence determined by N-terminal Edman degradation. In order to ensure that only the "coding" strand is sequenced, it is essential that the N-terminus of the "binding" strand be acetylated or otherwise made non- sequencable.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Analytical Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Peptides Or Proteins (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Graft Or Block Polymers (AREA)
Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US98827892A | 1992-12-11 | 1992-12-11 | |
US988278 | 1992-12-11 | ||
PCT/US1993/012013 WO1994013623A1 (fr) | 1992-12-11 | 1993-12-10 | Synthese de polymeres codes |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0675873A1 true EP0675873A1 (fr) | 1995-10-11 |
EP0675873A4 EP0675873A4 (fr) | 2000-03-29 |
Family
ID=25534002
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP94904077A Withdrawn EP0675873A4 (fr) | 1992-12-11 | 1993-12-10 | Synthese de polymeres codes |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0675873A4 (fr) |
JP (1) | JPH08504444A (fr) |
AU (1) | AU5827294A (fr) |
CA (1) | CA2151473A1 (fr) |
WO (1) | WO1994013623A1 (fr) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5527675A (en) * | 1993-08-20 | 1996-06-18 | Millipore Corporation | Method for degradation and sequencing of polymers which sequentially eliminate terminal residues |
US5776737A (en) * | 1994-12-22 | 1998-07-07 | Visible Genetics Inc. | Method and composition for internal identification of samples |
GB9502225D0 (en) * | 1995-02-04 | 1995-03-22 | Zeneca Ltd | Method |
US6284459B1 (en) | 1995-04-25 | 2001-09-04 | Discovery Partners International | Solid support matrices with memories and combinatorial libraries therefrom |
US5961923A (en) * | 1995-04-25 | 1999-10-05 | Irori | Matrices with memories and uses thereof |
US6100026A (en) * | 1995-04-25 | 2000-08-08 | Irori | Matrices with memories and uses thereof |
GB9515070D0 (en) * | 1995-07-22 | 1995-09-20 | Zeneca Ltd | Label |
ATE556149T1 (de) * | 1999-02-23 | 2012-05-15 | Caliper Life Sciences Inc | Manipulation von mikropartikeln in mikrofluidischen systemen |
DE10041238A1 (de) * | 2000-08-22 | 2002-03-07 | Aventis Res & Tech Gmbh & Co | Verfahren zur Identifizierung spezifisch spaltbarer peptide und Verwendung solcher Peptidsequenzen |
WO2002052046A2 (fr) | 2000-12-23 | 2002-07-04 | Chiron Corporation | Procede de criblage et de transfection d'oligonucleotides |
US7727713B2 (en) | 2001-06-20 | 2010-06-01 | Nuevolution A/S | Templated molecules and methods for using such molecules |
AU2003214031A1 (en) | 2002-03-15 | 2003-09-29 | Nuevolution A/S | An improved method for synthesising templated molecules |
AU2003247266A1 (en) | 2002-08-01 | 2004-02-23 | Nuevolution A/S | Multi-step synthesis of templated molecules |
NZ538993A (en) | 2002-10-30 | 2008-04-30 | Nuevolution As | Method for the synthesis of a bifunctional complex |
ATE450609T1 (de) | 2002-12-19 | 2009-12-15 | Nuevolution As | Durch quasizufallsstrukturen und funktionen geführte synthesemethode |
US20070026397A1 (en) | 2003-02-21 | 2007-02-01 | Nuevolution A/S | Method for producing second-generation library |
WO2004099441A2 (fr) * | 2003-05-09 | 2004-11-18 | Hyscite Discovery As | Selection et developpement de bibliotheques chimiques |
ATE447626T1 (de) | 2003-09-18 | 2009-11-15 | Nuevolution As | Methode zur gewinnung struktureller informationen kodierter moleküle und zur selektion von verbindungen |
NZ547723A (en) * | 2003-12-17 | 2009-09-25 | Praecis Pharm Inc | Methods for synthesis of encoded libraries |
US7972994B2 (en) | 2003-12-17 | 2011-07-05 | Glaxosmithkline Llc | Methods for synthesis of encoded libraries |
WO2006135786A2 (fr) | 2005-06-09 | 2006-12-21 | Praecis Pharmaceuticals, Inc. | Procedes de synthese de bibliotheques codees |
CA2626325A1 (fr) * | 2005-10-28 | 2007-05-10 | Praecis Pharmaceuticals Incorporated | Procedes d'identification de composes etudies, par recours a des bibliotheques codees |
DK3018206T3 (da) | 2005-12-01 | 2021-11-15 | Nuevolution As | Enzymatic encoding methods for efficient synthesis of large libraries |
ES2713873T3 (es) | 2010-04-16 | 2019-05-24 | Nuevolution As | Complejos bifuncionales y métodos para hacer y utilizar tales complejos |
US10760181B2 (en) | 2015-02-24 | 2020-09-01 | City Of Hope | Chemically encoded spatially addressed library screening platforms |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993006121A1 (fr) * | 1991-09-18 | 1993-04-01 | Affymax Technologies N.V. | Procede de synthese de diverses collections d'oligomeres |
WO1994008051A1 (fr) * | 1992-10-01 | 1994-04-14 | The Trustees Of Columbia University In The City Of New York | Banques chimiques combinatoires complexes codees avec des etiquettes |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4359353A (en) * | 1981-05-18 | 1982-11-16 | Hydrocarbon Research, Inc. | Polypeptides as chemical tagging materials |
-
1993
- 1993-12-10 EP EP94904077A patent/EP0675873A4/fr not_active Withdrawn
- 1993-12-10 WO PCT/US1993/012013 patent/WO1994013623A1/fr not_active Application Discontinuation
- 1993-12-10 CA CA 2151473 patent/CA2151473A1/fr not_active Abandoned
- 1993-12-10 JP JP6514425A patent/JPH08504444A/ja not_active Withdrawn
- 1993-12-10 AU AU58272/94A patent/AU5827294A/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993006121A1 (fr) * | 1991-09-18 | 1993-04-01 | Affymax Technologies N.V. | Procede de synthese de diverses collections d'oligomeres |
WO1994008051A1 (fr) * | 1992-10-01 | 1994-04-14 | The Trustees Of Columbia University In The City Of New York | Banques chimiques combinatoires complexes codees avec des etiquettes |
Non-Patent Citations (4)
Title |
---|
J. NIELSEN ET AL.: "Synthetic Methods for the Implementation of Encoded Combinatorial Chemistry" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 115, 3 November 1993 (1993-11-03), pages 9812-9813, XP002128604 DC US * |
J.M. KERR ET AL.: "Encoded Combinatorial Peptide Libraries Containing Non-Natural Amino Acids" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 115, 24 March 1993 (1993-03-24), pages 2529-2531, XP002128603 DC US * |
R.J. SIMON ET AL.: "Peptoids: A modular approach to drug discovery" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, vol. 89, October 1992 (1992-10), pages 9367-9371, XP002128602 WASHINGTON US * |
See also references of WO9413623A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1994013623A1 (fr) | 1994-06-23 |
JPH08504444A (ja) | 1996-05-14 |
CA2151473A1 (fr) | 1994-06-23 |
AU5827294A (en) | 1994-07-04 |
EP0675873A4 (fr) | 2000-03-29 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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17P | Request for examination filed |
Effective date: 19950710 |
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AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB IE IT LI LU MC NL PT SE |
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RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: KERR, JANICE M. Inventor name: ZUCKERMANN, RONALD N. |
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A4 | Supplementary search report drawn up and despatched |
Effective date: 20000210 |
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AK | Designated contracting states |
Kind code of ref document: A4 Designated state(s): AT BE CH DE DK ES FR GB IE IT LI LU MC NL PT SE |
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STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
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18W | Application withdrawn |
Withdrawal date: 20000426 |