EP0675873A1 - Synthese de polymeres codes - Google Patents

Synthese de polymeres codes

Info

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Withdrawn
Application number
EP94904077A
Other languages
German (de)
English (en)
Other versions
EP0675873A4 (fr
Inventor
Ronald N. Zuckermann
Janice M. Kerr
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Vaccines and Diagnostics Inc
Original Assignee
Chiron Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Chiron Corp filed Critical Chiron Corp
Publication of EP0675873A1 publication Critical patent/EP0675873A1/fr
Publication of EP0675873A4 publication Critical patent/EP0675873A4/fr
Withdrawn legal-status Critical Current

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

L'invention concerne des conjugués et des procédés de production de ces conjugués et de mélanges de ceux-ci. Des conjugués comprennent un polymère actif constitué de motifs monomères choisis dans le groupe comprenant les unités monomères de peptides et/ou de peptoïdes, un polymère codant constitué de monomères codants, ledit polymère codant correspondant au polymère actif, ainsi qu'une fraction de couplage couplée par covalence au polymère actif et au polymère codant. Conformément à la méthodologie relative à la synthèse de polymères, des mélanges comprenant un grand nombre de conjugués sont obtenus au moyen d'une fraction de couplage qui est liée par covalence à un monomère actif et à un monomère codant. Des motifs monomères supplémentaires sont ajoutés au monomère actif pour créer un polymère actif, et des motifs monomères supplémentaires sont ajoutés au monomère codant pour produire un polymère codant jusqu'à obtention de la longueur désirée pour le polymère actif. Des mélanges de conjugués fixés à des bases de support peuvent être utilisés pour analyser un échantillon. L'échantillon est mis en contact avec les conjugés et l'on détermine quelles protéines actives se lient au site récepteur dans l'échantillon. Lorsqu'il est déterminé que ce sont des protéines actives, le polymère codant associé au polymère actif est séquencé, et, par déduction, l'on détermine la séquence du polymère actif.
EP94904077A 1992-12-11 1993-12-10 Synthese de polymeres codes Withdrawn EP0675873A4 (fr)

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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4359353A (en) * 1981-05-18 1982-11-16 Hydrocarbon Research, Inc. Polypeptides as chemical tagging materials

Patent Citations (2)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

Similar Documents

Publication Publication Date Title
WO1994013623A1 (fr) Synthese de polymeres codes
Lebl et al. One‐bead–one‐structure combinatorial libraries
EP0705279B1 (fr) Banques en phase solide codees a segregation topoligique
Jung et al. Multiple peptide synthesis methods and their applications. New synthetic methods (87)
US5840485A (en) Topologically segregated, encoded solid phase libraries
Pavia et al. The generation of molecular diversity
Hudson Matrix assisted synthetic transformations: a mosaic of diverse contributions. II. The pattern is completed
Lowe Combinatorial chemistry
US5541061A (en) Methods for screening factorial chemical libraries
US5510240A (en) Method of screening a peptide library
US20030228605A1 (en) Identification of protein binding sites
Dower et al. The search for molecular diversity (II): recombinant and synthetic randomized peptide libraries
TW201124726A (en) Compositions and methods for producing coded peptoid libraries
Ede Multiple parallel synthesis of peptides on SynPhase™ grafted supports
Beck-Sickinger et al. Combinatorial strategies in biology and chemistry
US6864048B2 (en) Factorial chemical libraries
Groth et al. PEG based resins for protease drug discovery synthesis, screening and analysis of combinatorial on-bead libraries
US5846841A (en) Motif Libraries
Kushwaha et al. A Novel Methods Used in Drug Discovery
Lebl et al. Felder zyxwvutsrqponmlkj
Marasco Synthetic Peptide Libraries: Chemical Diversity to Reach Lead Compounds
Krchňák et al. 2 Combinatorial Libraries of Synthetic Structures: Synthesis, Screening, and Structure Determination
WO2006018277A1 (fr) Procede de synthese combinatoire rationnelle
Lam et al. 6 Combinatorial Library Based on the One-Bead-One-Compound Concept
Handbook Combinatorial Peptide and Nonpeptide Libraries

Legal Events

Date Code Title Description
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

17P Request for examination filed

Effective date: 19950710

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

RIN1 Information on inventor provided before grant (corrected)

Inventor name: KERR, JANICE M.

Inventor name: ZUCKERMANN, RONALD N.

A4 Supplementary search report drawn up and despatched

Effective date: 20000210

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

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Withdrawal date: 20000426