Herein is an abbreviated patent application, filing date Dec 30 2003, wherein is described novel ligand-conjugated polynucleotides, combinatorial libraries thereof, and microarrays of the members of these combinatorial libraries. These species, termed Polygands (derived from POLYnucleotide-conjugated liGAND) have considerable and novel utility, including use as bioactive agents particularly drugs, in diagnostics, and in regioselective and/or stereoselective chemical syntheses.

BACKGROUND OF INVENTION

Tyagi, et al (US Patent 5,925,517) teach hairpin duplexes whose 3' and 5' termini are conjugated to a labels, preferably fluorescent. Labels are not considered ligands as defined herein.

Cantor, et al (US Patent 5,849,878) & Niemeyer, et al (US Patent Appl 20030118595) teach helixes of ligand-conjugated nucleic acids, wherein ligands are longitudinally (relative to the axis of the helix) conjugated at opposite ends of the duplex.

Kruz, et al (US Patent Appl 20030027194) primarily teach multimers of a relatively large protein-conjugated RNA. The proteins of such a multimer are preferably complementary so as to form antibody Fab-like or zinc-finger-like receptors. In each and every of the extensive examples, the protein is conjugated to the 3' end. This is do to the preference that the RNA encodes for its conjugated protein. The consequence of all the proteins conjugated to 3' termini is that two such conjugates cannot hybridize to each other to form one antiparallel linear helix and a lateral grouping of ligands. As Cantor, et al & Niemeyer, et al the self-hybridized helixes they form result in the conjugated proteins being longitudinally positioned relative to the helix axis (their Drawing Sheet 1). For two proteins to be laterally grouped, Kruz, et al require a third associating polynucleotide which hybridizes to both protein-conjugated RNAs (their Drawing Sheets 2 & 3).

In contrast to the relatively large receptor protein complexes which are the primary focus of Kruz, et al, the primary objective of the present invention is the design of smaller receptor-binding ligand therapeutics. They do not specify using ligands other than proteins, nor even polypeptides with non-peotide linkages.

Further their preferred means of complexation is through carefully designed cooperative multiermization domains on the proteins (their Drawing sheets 4, 5, 6 & 8). The ligands of the present invention are not designed to cooperatively bind each other in such a fashion.

They do not specify encoded or support-affixed combinatorial libraries, particularly those which are arrayed. Nor do they specify utilizing multimers in regioselective and/or stereoselective syntheses. Finally, and perhaps most importantly, they do not specify therapeutic utility of the conjugated polynucleotides, particularly as small bioactive nucleic acids.

DRAWINGS

Figures 1A, 1B & 1C. Ligand-conjugated polynucleotides.
Figures 1D & 1E. Two relatively simple polygands.

--------------------

Figures 2A-2E. Examples of polygands comprising a multitude of ligand-conjugated polynucleotides.

--------------------

Figures 3A & 3B. Formation of polygand hairpin libraries, one of which is arrayed.

--------------------

Figures 4A & 4B. Formation and utility of combinatorial polygands and their arrays.

--------------------

Figure 5 A. Polygand bound to a target via two ligand-binding sites.
Figure 5B. Polygand whose composite decoy small bioactive nucleic acid is facilitated in its target binding by the terminally grouped ligands.

--------------------

Figure 6. Polygand whose two identical ligands bind to two identical receptors so as to bring them into proximity.

--------------------

Figure 7. Supramolecular assembly of polygands.

--------------------

Figures 8A-8D. Polygands functioning in regioselective and/or stereoselective reactions.

--------------------

Figure 9. Generalization of utilizing complexing modules, in a combinatorial fashion, to bring conjugated ligands into proximity.

--------------------

While these figures show many of the essential characteristics of the invention herein, they are hypothetical and highly schematic sketches which are not exactly to scale.

DETAILED DESCRIPTION OF INVENTION

A "molecule" is the smallest particle of a substance that retains all the properties of the substance and is composed of one or more atoms. The atoms of a "covalent molecule" are linked by covalent bonds.

A "biomolecule" is a molecule present within a virus, cell or organism.

A "target" is a molecule, most often a biomolecule.

A "bioactive" molecule binds a specific biomolecular target(s), and in so doing alters biological functioning. Preferably a bioactive molecule is a drug or is used as a lead in the development of a drug.

The term "ligand" as used herein is any molecule which does not comprise a nucleotide(s), nor is a known label. A known "label" is any molecule which has been specifically utilized in the detection and/or identification a conjugated entity. Most commonly these labels involve fluorescence.

Ligand examples include polypeptides, carbohydrate polymers and derivatives thereof, and nonpolymeric small organic molecules. Ligands are commonly know to bind biomolecular targets, which are often but not necessary larger than the ligands. However, since the invention herein also has utility in regiospecific and/or stereospecific syntheses, a "ligand" can also be selected or designed to function in a chemical reaction.

A "polynucleotide" is a single-stranded molecular polymer of any length whose nucleotide monomer side-groups can match up (hybridize) with those of a complementary polynucleotide to form a linear helix (i.e., duplex, triplex, quadruplex etc.) of relatively constant width. It is understood that a helix need not consist of perfectly complementary polynucleotides, and that mispairs may occur to a limited extent. Polynucleotides utilized herein are preferably 5-50 nucleotides in length. There are a vast number of known and conceivable nucleotide monomers, and polymerized combinations thereof. Relatively short polynucleotides are often calls oligonucleotides or oligos. Polynucleotides and their vast number of known and possible nucleotide derivations such as peptide nucleic acids, are particularly valuable because of their inherent encoding of readily accessible information. Furthermore, polynucleotides and their rigid helixes can be designed to be relatively featureless, unreactive, durable and of variable hydrophobicity, making them compatible with various solvents and chemical processes, and excellent ligand scaffolds. A "nucleic acid" consists of one or more polynucleotides. Of course, naturally occurring single-stranded and double-stranded DNA and RNA are nucleic acids.

Polynucleotides can be bioactive, and those of particular interest are the "small bioactive nucleic acids", each of which is defined as a polynucleotide or polynucleotide helix of preferably less than 50 nucleotides in length, and whose target is a nucleic acid or a biomolecule which binds a nucleic acid . The most important small bioactive nucleic acids are 1) antisense oligonucleotides (including ribonuclease L-activating; triplex-forming (TFO); and those formulated into a helix) 2) small interfering RNA (siRNA), 3) small hairpin RNA (shRNA), 4) decoys, 5) chimeric RNA/DNA oligonucleotides.

Worthy of clarification are the polyamides whose backbones comprise heterocycles, such as pyrrole and imidazole. While they complex with polynucleotide helixes, they are not considered polynucleotides as defined herein.

A "polypeptide" is a molecular polymer of any length whose monomer linkages may or may not be peptide bonds, and whose side groups are selected from at least the more than twenty naturally occurring amino acid side groups such as glycine, alanine, and tyrosine. Although the distinction between polynucleotides and polypeptides is becoming less clear with time, for the purposes herein, polypeptides are distinguished from polynucleotides in the lack of complementarity of their side groups and consequent inability to form linear duplexes. Numerous unnatural modifications to both the amine linkages and side groups are known. "Proteins" are naturally occurring polypeptides wherein all the monomers are linked via peptide bonds.

"Nonpolymeric organic molecules" which are mostly covalent include a vast number both natural and synthetic.

A entity is "distinct" when in some intrinsic characteristic it is different from others. For clarity, when describing a process involving a mixture of distinct molecules, only one of each distinct molecule is being referred to. An unqualified statement such as "molecules" optionally indicates multitude which are identical or distinct.

The essence of this invention is a "polygand" (derived from POLYnucleotide-conjugated liGAND) which can be defined as

i) one ligand-conjugated polynucleotide self-hybridized to form a linear helix and a lateral grouping of ligands, or

ii) two complementary ligand-conjugated polynucleotides hybridized to each other to form a linear helix and a lateral grouping of ligands, or

iii) one or two complementary polynucleotides hybridized to form a linear antiparallel duplex whose 3' and 5' terminal nucleotides at one end are each conjugated to a terminus of one polypeptide ligand.

Conjugation can be accomplished by directly linking a ligand to a polynucleotide. Alternatively a ligand-conjugated polynucleotide could be completely synthesized by step-wise addition of monomers; or one domain of a ligand-conjugated polynucleotide, such as the polynucleotide, could be used as a starting point for the stepwise synthesis of the ligand. Ligand conjugation to a polynucleotide can be through a liinker, perhaps cleavable. A is preferably conjugated to the very last nucleotide, and the statement "conjugated to the 3' and 5' terminal nucleotides" indicates that a ligand is conjugated to the last nucleotide, which includes the first internucleotide linkage.

Polynucleotide conjugation is an active research area and there are many valuable reports thereof.

One of the simplest polygands is composed of one ligand-conjugated polynucleotide whose polynucleotide termini are each conjugated to separate often distinct ligand, and which being self complementary has hybridized into a hairpin duplex so as to form a lateral grouping of ligands at one end (Figure 1D).

Ligands are "laterally grouped" when the distance between the points along the helix to which they are conjugated to is less than the length of the helix.

Another simple polygand comprises a linear duplex whose 3' and 5' termini at one end are each conjugated to a terminus of one biomolecular polymer, preferably a polypeptide (Figure 1E). Such a single polypeptide, while potentially branched, has a contiguous amide bond backbone the ends of which are conjugated to the polynucleotide termini. The polynucleotide termini at the end distal the ligand(s), if not in a hairpin, could be adjoined and stabilized by a chemical linker.

As exemplified in Figure 1D and those to follow, the "grouped ligands" of a polygand are proximate relative to the length of the helix. Preferably grouped ligands are in contact or less than about 10 Angstroms apart when in solution and not bound to target(s).

Examples of complex polygands with multiple ligand-conjugated polynucleotides are sketched out in Drawing Sheet 2. In Figure 2A the laterally grouped ligands are in contact and form a ligand dimer. Note the optional single-stranded polynucleotide tail, which can have several utilities including being a bioactive antisense or triplix-forming oligonucleotide, or function to encode the identity of the conjugated ligand. In Figure 2B the two grouped ligands are nonpolymeric organic molecules. Figure 2C is a triplex of ligand-conjugated polynucleotides with one ligand being a cyclic polymer. In Figure 2D two ligand-conjugated polynucleotides have hybridized with a template for form a triplex. In the final figure Figure 2E the ligands are conjugated at internal sites along the polynucleotides, one being a branched polymer attached at two locations.

Of paramount importance to the present invention are combinatorial libraries of polygands, and their method of synthesis. Each member of these libraries has distinct grouping of ligands (the set of ligand types for each member is unique).

Figure 3A exemplifies a solution phase method of constructing a library of hairpin polygands, while Figure 3B exemplifies the use of photolithography and arrays.

More specifically, in Figure 3A, we start with three identical denatured hairpin polynucleotides in solution, while in Figure 3B we have 3 identical hairpin polynucleotides affixed to three loci on the surface of a small section of an array (only one probe is shown at each of the three array loci). One end of these identical hairpin polynucleotides is first subjected to the split-pool synthesis approach or to photolithography, resulting in polynucleotides with distinct ligands. The unconjugated polynucleotide termini of each of the resultant distinct library members is then conjugated to a common ligand, or alternatively to a set of distinct ligands. If desired it is possible to sever the duplexes close to the hairpin loops, such as by a restriction enzyme. Many other schemes to produce such a combinatorial library of hairpins, each member of which having a distinct set of grouped ligands, could be devised.

Construction of a combinatorial library of two stranded duplex polygands is sketched out in Figure 4A & 4B. In Figure 4A, three ligand-conjugated polynucleotides with distinct ligands and identical polynucleotides are affixed to three loci on the surface of a small section of an array. Note the small stem-loop hairpin at the base of probes. Simply by hybridizing identical ligand-conjugated polynucleotides to each distinct affixed ligand-conjugated polynucleotide, followed by ligation, one can create a large variety of very stable combinatorial ligand dimers. Note the resemblance of these polygands to the hairpins of Figure 3B. Another means of stabilization would be by crosslinking hybridized polynucleotides, such as by a psoralen or nucleotide base derivative.

In Figure 4B, a combinatorial library of duplex polygands are first formed in solution by combining the appropriate ligand-conjugated polynucleotides one of which has both a distinct ligand and an encoded polynucleotide tail. These complexes are subsequently contacted with a target, and then hybridized via the encoded tails to a "universal addressable array". By localizing the target in the array the binding polygand is identified. Alternatively, the target could be contacted to previously addressed polygands.

Besides identifying target-binding polygands utilizing the arrays, another method of screening involves contacting a target (perhaps present on a bead, in a cell or a particular organ) with a soluble polygand mixture, each distinct polygand having an encoded tail. Subsequent to washing unbound polygands, those bound could be identified via their encoded tails utilizing various techniques, including addressing to an array or a primer-based amplification such as PCR or rolling circle amplification.

Yet another interesting means of screening depends on the capacity of polygands, comprised of a small bioactive nucleic acid, to trigger the cellular expression or repression of a label such as green fluorescent protein. Individual assays for each polygand library member would identify ligands which facilitated functioning of the label-triggering small bioactive nucleic acid.

Once identified these facilitating ligands could be transferred to other bioactive agents, particularly therapeutic small bioactive nucleic acids directed to nucleic acid targets. Alternatively such a facilitating ligands could be conjugated in an identical manner to a set of polygands with distinct helix sequences.

Worthy of mention is work utilizing fluorescence in the study of whole life animals. By utilizing a fluorescent label-triggering small bioactive nucleic acid, once could examine the capacity of conjugated ligands to target this label-triggering small bioactive nucleic acid to a particular tissue or organ.

Of course, as with other molecular libraries, combinatorial libraries of polygands can be utilized in any of a large and ever increasing variety of screening processes. Of particular interest is a recently disclosed array-based process wherein two arrays are brought into close apposition such that reactants on the surfaces of two arrays come into contact, optionally involving liberation of support-affixed reagents. A process wherein an array of polygands are in mass liberated from a support so as to be contacted with target in solution is likewise envisioned.

Combinatorial libraries can be screened for target-binding and/or bioactivity, which may be inherent in the ligands and/or in the polynucleotides. Currently there is intense research into small bioactive nucleic acids, with particular focus on drug development. Of paramount importance to the present invention is to identify conjugated ligands which facilitate the functioning of these exceptionally promising short bioactive helixes.

Another objective of current drug research is the advantageous linking of two target-binding molecules, either directed to the same target so as to increase a drug's affinity or specificity, or to separate targets which when associated result in bioactivity. One or both target-binding molecules may be known drugs. This objective is also that of the present invention. For example in Figure 5A one polygand binds at two loci in one target; note the capacity of a polynucleotide duplex terminus to dynamically break and reform base-pairs ("breath"), the relative positioning of ligands in polygands has more degrees of freedom. Note also the lack of ligand cooperatively via their contacting each other. Once such a complex is identified it could be utilized to design a covalently linking group which could replace the polynucleotides is correctly positioning the ligands.

A certain process for discovering target binding multimers, particularly dimers, is termed "Dynamic Combinatorial Chemistry" Therein different molecules are brought in to dynamic equilibrium in the present of their target, so as to effect target-induced coupling. A derivation of this process utilizing polygands would be wherein the dynamic equilibrium was effected by noncovalent hybridizations/denaturations of ligand-conjugated polynucleotides. The polygand of Figure 5 could well have be created via such a dynamic combinatorial library.

In Figure 5B a ligand grouping is facilitating the binding of a decoy small bioactive nucleic acid to its transcription factor receptor.

In Figure 6, identical ligands have independently bound to identical, previously unassociated target receptors brining them into proximity. Many cell surface receptors become active signaling complexes when brought into such proximity.

Note the similarity of certain polygands to antibody Fab fragments, and the truly vast number of combinations possible. Such combinatorial ligand libraries are of paramount importance, particularly for use in selecting polygands which specifically bind to a biomolecular target and have therapeutic potential. Recognize further that essentially all antibody-based technology, including diagnostics, can be analogously applied to polygands or complexes thereof. Figure 7 exemplifies such a complex wherein three polygands bound to ligands have been hybridized to a branched polynucleotide template. Many more complexes, both noncovalent and covalent, with varying degrees of distinct polygands and hybridization templates can be imagined.

Utility of polygands as a synthetic tool is also of paramount importance. In hypothetical polygands of Figure 8A & 8B the two hypothetical ligands are being regioselectively coupled via a disulfide bond and coupling agent, respectively. In Figure 8C two hypothetical nonpolymeric organic molecules are reacting in a stereoselective manner. To prevent interpolygand reactions the polygands could be relatively dilute in concentration, or alternatively could be sparsely affixed to a support.

In the last reaction of Figure 8D one of the ligands is a kinase which when provided with ATP regioselectively phophosphorylates the proximal ligand. As an alternative to this intrapolygand enzymatic reaction, a polygand could act as a catalyst covalently modifying multiple substrates.

Conceivably, simply bringing the ligands into proximity could cause their reaction. Of course numerous other reactions, involving a vast number of molecules, could be envisioned.

Of course the particular type of polynucleotide, that is its chemical makeup, and the means of conjugation is preferably inert to the ligand reaction.

It is interesting to compare reactive polygands with commonly encountered enzymes; instead of one enzyme bringing two reagents into proximity, two polynucleotides are performing this function.

Note the utility of combinatorial libraries of polygands in multiplex syntheses, reactions being performed in parallel.

Note also this would increase the diversity of these polygand libraries so as to further the possibility of target binding.

Ligands could be conjugated to the polynucleotides so that they or their product(s) are capable of liberation. This would be valuable, for example, for solution screening of a library of regioselective ligand products.

Such reactive polygands as exemplified in Figures 8A-8D represent an invention of much broader scope, wherein the polynucleotides of a polygand are representative of "complexing modules" in general. The species of this invention can be characterized as a multitude of ligand-conjugated complexing modules, which when said modules complex they bring their conjugated ligands into proximity conducive to performing a chemical reaction, preferably regioselective and/or stereoselective. Figure 9 is a generalization of forming such species in a combinatorial fashion.

NOTE

These examples and accompanying figures have deliberately been made exceptionally simple so as to clearly and concisely present the invention. Many modifications and variations of the present invention are possible, and it is intended that all such modifications and variations be included within the scope of present invention as defined by the claims.

CLAIMS

1) A polygand which prior to contacting a target comprises either

i) two complementary ligand-conjugated polynucleotides stably hybridized to each other to form linear antiparallel duplex and a lateral grouping of proximal ligands; or
ii) two complementary polynucleotides conjugated to the same polypeptide comprising ligand and stably hybridized to each to form a linear antiparallel duplex.

conjugated to separate ligands, or to the same polypeptide-comprising ligand.

4) The polygand of claim 1 wherein the ligands are covalently crosslinked subsequent to being brought into proximity.

5) The polygand of claim 1, wherein

i) at least one ligand is a polypeptide, or
ii) one ligand is a polypeptide and one ligand is not, or
iii) at least one ligand is not a protein, or
vi) at least one ligand is a nonpolymeric organic molecule, or
v) at least one ligand is known to independently bind a specific cellular target, or
vi) at least one ligand is known to independently have a specific bioactivity.

7) The set of probes described by claim 5, wherein each probe is support-affixed.

8) The library of polygands of claim 6, each member being support-affixed.

9) The polygand of claim 1 which contains a small bioactive nucleic acid.

10) A library of small bioactive nucleic acids of claim 9, each member being distinct in type of ligand(s) present.

11) A chemical reaction product of the polygand of claim 1.

12) Chemical reaction products of the polygands of the library of claim 6. 13) A library of support-affixed polynucleotide helixes each member being conjugated to a distinct set of at least two separate ligands.

14) A complex comprising a multitude of polygands.

15) A small bioactive nucleic acid present within, or conjugated to, a linear polynucleotide helix

i) conjugated to a multitude of distinct ligands, or
ii) whose 3' and 5' terminal nucleotides at one end are each conjugated to a terminus of one contiguous polypeptide ligand, said ligand(s) facilitating the functioning of the small bioactive nucleic acid.

17) A complex for performing a regioselective and/or stereoselective chemical reaction comprised of a multitude of ligand-conjugated complexing modules, which when said modules complex, their conjugated ligands are brought into proximity conducive to performing said reaction; provided that

i) at least one ligand is not a protein, or
ii) at least one ligand is not a polypeptide, or
iii) at least one ligand is a polypeptide and one ligand is not, or
iv) at least one ligand is a nonpolymeric organic molecule, or
v) the ligands do not become cross-linked, or
vi) the reaction is stereospecific.

References:

Detectably labeled dual conformation oligonucleotide probes, assays and kits. US Patent 5,925,517 Tyagi, et al July 20, 1999

Antiviral polynucleotide conjugates. US Patent 5,495,006 Climie, et al. February 27, 1996

Design and synthesis of bispecific reagents: use of double stranded DNAs as chemically and spatially defined cross-linkers. Cantor, et al. US Patent 5,849,878 December 15, 1998

Supramolecular bioconjugates. US Patent Appl 20030118595 Niemeyer CM, et al. June 26, 2003

Modular assembly of nucleic acid-protein fusion multimers. US Patent Appl 20030027194 Kruz M, et al February 6, 2003

Recent Advances in Nucleosides: Chemistry and Chemotherapy. Editor Chung K. Chu (2002) Elsevier Health Sciences

Applied Antisense Oligonucleotide Technology. Editors Stein CA & Krieg AM (1998) Wiley-Liss

Pharmaceutical Aspects of Oligonucleotides. Editors Patrick Couvreur P & Claude Malvy C (1999) Taylor & Francis

Protocols for Oligonucleotides and Analogs: Synthesis and Properties (Methods in Molecular Biology, 20). Editor Agrawal S (1993) Humana Press; (December 1993)

Synthetic Oligonucleotides: Preparation, Analysis and Applications. F.M. Vega FM & Guarneros G (1996) Springer-Verlag Berlin and Heidelberg GmbH & Co. KG

Oligonucleotides and Analogues: A Practical Approach (The Practical Approach Series). Editor Echstein F (1992) Oxford University Press

Delivery Strategies for Antisense Oligonucleotide Therapeutics. Editor Saghir Akhtar S (1995) CRC Press

Therapeutic Applications of Oligonucleotides. Crooke ST (1995) Landes Bioscience

Nucleoside Mimetics: Their Chemistry and Biological Properties (Advanced Chemistry Texts) Claire Simons C & Simons C (2000) Taylor & Francis;

Frontiers in Nucleic Acid Chemistry. Eitors Kisakürek MV & Rosemeyer H (2001) Wiley-VCH

Chemistry of Nucleosides and Nucleotides / Editor Townsend, LB (1991) Plenum Pr; (June 1991)

Handbook of Nucleoside Synthesis. Vorbrüggen H & Ruh-Pohlenz (2001) Wiley-Interscience

Nucleoside analogues : chemistry, biology, and medical applications. Eitors Richard T. Walker RT, de Clercq E, & Eckstein, F New York : Plenum Press, c1979

Oligonucleotides and analogues : a practical approach. Eitor Eckstein F (1991) Oxford ; New York : IRL Press

Design and applications of modified oligonucleotides. (review) Gallo M, et al Braz J Med Biol Res. 2003 Feb;36(2):143-51

Oligonucleotides and Analogues. A Practical Approach. Eckstein F (1991) IRL Press Oxford.

Oligonucleotide analogues. US Patent 6,670,461 Wengel, et al. December 30, 2003

Novel phosphoramidite building blocks in synthesis and applications toward modified oligonucleotides. (review) Venkatesan N, et al Curr Med Chem. 2003 Oct;10(19):1973-91

Bicyclonucleoside and oligonucleotide analogues. US Patent 6,268,490 Imanishi, et al. July 31, 2001

Difference in conformational diversity between nucleic acids with a six-membered Osugar¹ unit and natural Ofuranose¹ nucleic acids. Lescrinier, et al Nucleic Acids Research (2003) 31(12):2975-2989

Double-stranded peptide nucleic acids. US Patent Appl 20030232355 Norden Benget, et al. December 18, 2003

Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines. US Patent Appl 20030096980 Froehler B, et al. May 22, 2003

Oligonucleotides having chiral phosphorus linkages US Patent 5,852,188 Cook December 22, 1998

Mimicking the Structure and Function of DNA: Insights into DNA Stability and Replication. Kool ET,et al Angew Chem Int Ed Engl 2000 Mar;39(6):990-1009

Replication of non-hydrogen bonded bases by DNA polymerases: a mechanism for steric matching. Kool ET Biopolymers 1998;48(1):3-17

Stem-loop oligonucleotides: a robust tool for molecular biology and biotechnology. (review) Broude NE. Trends Biotechnol. 2002 Jun;20(6):249-56

Triplex DNA structures. (review) Frank-Kamenetskii MD, et al Annu Rev Biochem. 1995;64:65-95

Absolute bioavailability of 2'-O-(2-methoxyethyl)-modified antisense oligonucleotides following intraduodenal instillation in rats. Geary RS, et al J Pharmacol Exp Ther. 2001 Mar;296(3):898-904

Pulmonary bioavailability of a phosphorothioate oligonucleotide (CGP 64128A): comparison with other delivery routes. Nicklin PL, et al Pharm Res. 1998 Apr;15(4):583-91

Nucleic acid multiplex formation. US Patent Appl 20030113716 Erikson GH, et al. June 19, 2003

PNA synthesis using a base-labile amino protecting group. US Patent 6,316,595 Breipohl, et al. November 13, 2001

Method for placing a photo-cross-linking agent at specific internal sites within the sequence of synthetic strands of ribonucleic acids US Patent 6,124,099 Heckman , et al. September 26, 2000

Oligonucleotide-cyclopropapyrroloindole conjugates as sequence specific hybridization and crosslinking agents for nucleic acids. US Patent 5,659,022 Kutyavin, et al. August 19, 1997

A novel combined chemical-enzymatic synthesis of cross-linked DNA using a nucleoside triphosphate analogue. Cowart M, et al Biochemistry 1991 Jan 22;30(3):788-96

Rapid and efficient hybridization-triggered crosslinking within a DNA duplex by an oligodeoxyribonucleotide bearing a conjugated cyclopropapyrroloindole. Lukhtanov EA, et al Nucleic Acids Res 1996 Feb 15;24(4):683-7

Oligonucleotides: Antisense, Rnai, Triple-Helix, Gene Repair, Enhancer Decoys, Cpg, and DNA Chips (Annals of the New York Academy of Sciences, Vol 1002). / (2004) Editors Stein CA, Cho-Chung YS & Gewirtz, AM New York Academy of Sciences

Pharmaceutical aspects of oligonucleotides. Eitor Couvreur P & Malvy C (2000) London ; Philadelphia, PA : Taylor & Francis

SBH Prospects for antisense nucleic acid therapy of cancer and AIDS. Eitor Wickstrom E (1991) New York : Wiley-Liss, c1991

Carbohydrate modifications in antisense therapeutics / Yogesh S. Sanghvi YS & Cook PD (1994) Washington, DC : American Chemical Society, 1994

Triple Helix Forming Oligonucleotides. Editors Claude Malvy C, Harel-Bellan A & Pritchard LL (1993) Kluwer Academic Publishers

Structural modifications of antisense oligonucleotides. (review) Urban E, et al Farmaco. 2003 Mar;58(3):243-58

Antisense properties of peptide nucleic acid. Larsen HJ, et al Biochim Biophys Acta. 1999 Dec 10;1489(1):159-66

Chimeric antisense oligonucleotides and cell transfecting formulations thereof. US Patent 6,677,445 Innis, et al January 13, 2004

Antisense oligonucleotides: basic concepts and mechanisms. (review) Dias N, et al Mol Cancer Ther. 2002 Mar;1(5):347-55

Clinical development of antisense oligonucleotides as anti-cancer therapeutics. (review) Chen HX Methods Mol Med. 2003;75:621-36

SBH Control of alternative splicing by antisense oligonucleotides as a potential chemotherapy: effects on gene expression. (review) Mercatante DR, et al Biochim Biophys Acta. 2002 Jul 18;1587(2-3):126-32

Antisense oligonucleotides: promise and reality. (review) Lebedeva I, et al Annu Rev Pharmacol Toxicol. 2001;41:403-19

Selective RNA cleavage by isolated RNase L activated with 2-5A antisense chimeric oligonucleotides. (review) Silverman RH, et al Methods Enzymol. 2000;313:522-33

Analysis of gene function in somatic mammalian cells using small interfering RNAs. Elbashir SM, et al Methods. 2002 Feb;26(2):199-213

Anti-HIV-1 activity of L-DNA quadruplex. Urata H, et al Nucleic Acids Res Suppl. 2002;(2):163-4

Antisense and RNAi: powerful tools in drug target discovery and validation. (review) Lavery KS, et al Curr Opin Drug Discov Devel. 2003 Jul;6(4):561-9

Antisense hairpin loop oligonucleotides as inhibitors of expression of multidrug resistance-associated protein 1: their stability in fetal calf serum and human plasma. Rebowski G, et al Acta Biochim Pol. 2001;48(4):1061-76

Antisense technologies. Improvement through novel chemical modifications. Kurreck J. Eur J Biochem. 2003 Apr;270(8):1628

Development of novel decoy oligonucleotides: advantages of circular dumb-bell decoy. (review) Tomita N, et al Curr Opin Mol Ther. 2003 Apr;5(2):107-12

Exploring plant genomes by RNA-induced gene silencing. (reveiw) Waterhouse PM, et al Nat Rev Genet. 2003 Jan;4(1):29-38

Exposing oncogenic dependencies for cancer drug target discovery and validation using RNAi. (review) Deveraux QL, et al Semin Cancer Biol. 2003 Aug;13(4):293-300

Gene repair and mutagenesis mediated by chimeric RNA-DNA oligonucleotides: chimeraplasty for gene therapy and conversion of single nucleotide polymorphisms. (review) Graham, et al Biochim Biophys Acta. 2002 May 21;1587(1):1-6

Gene silencing in mammals by small interfering RNAs. (review) McManus MT, et al Nat Rev Genet. 2002 Oct;3(10):737-47

Gene silencing mediated by small interfering RNAs in mammalian cells. (review) Scherr M, et al Curr Med Chem. 2003 Feb;10(3):245-56.

Gene therapy with transcription factor decoy oligonucleotides as a potential treatment for cardiovascular diseases. (review) Tomita N et al Curr Drug Targets. 2003 May;4(4):339-46

Hairpin RNAs and retrotransposon LTRs effect RNAi and chromatin-based gene silencing. Schramke V, et al Science. 2003 Aug 22;301(5636):1069-74

Interactions of hairpin oligo-2'-O-methylribonucleotides containing methylphosphonate linkages with HIV TAR RNA. Hamma T, et al Antisense Nucleic Acid Drug Dev. 2003 Feb;13(1):19-30

Mechanisms underlying targeted gene correction using chimeric RNA/DNA and single-stranded DNA oligonucleotides. (review) Anderson, et al J Mol Med. 2002 Dec;80(12):770-81

Oligonucleotide-based gene therapy for cardiovascular disease: are oligonucleotide therapeutics novel cardiovascular drugs? (review) Morishita R, et al Curr Drug Targets. 2000 Jul;1(1):15-23

Physico-chemical and biological properties of antisense phosphodiester oligonucleotides with various secondary structures. Maksimenko AV, et al Nucleosides Nucleotides. 1999 Sep;18(9):2071-91

Properties of nicked and circular dumbbell RNA/DNA chimeric oligonucleotides containing antisense phosphodiester oligodeoxynucleotides. Yamakawa H, et al Bioorg Med Chem. 1998 Jul;6(7):1025-3

Prospects of chimeric RNA-DNA oligonucleotides in gene therapy. (review) Wu XS, et al J Biomed Sci. 2001 Nov-Dec;8(6):439-45

Protozomics: trypanosomatid parasite genetics comes of age. (review) Beverley SM. Nat Rev Genet. 2003 Jan;4(1):11-9

Resistance of decoy PNA-DNA chimeras to enzymatic degradation in cellular extracts and serum. Borgatti, et al Oncol Res. 2003;13(5):279-87

Ribozymes and siRNA for the treatment of diseases of the nervous system. (review) Wood, et al Curr Opin Mol Ther. 2003 Aug;5(4):383-8

RNA interference machinery regulates chromosome dynamics during mitosis and meiosis in fission yeast. Hall IM, et al Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):193-8

RNA interference mediated inhibition of hepatitis B virus (HBV) using short interfering nucleic acid (siRNA. US Patent Appl 20030206887 Morrissey D, et al. November 6, 2003

RNA interference mediated inhibition of HIV gene expression using short interfering RNA. US Patent Appl 20030175950 McSwiggen JA September 18, 2003

RNA interference mediated inhibition of prostaglandin D2 receptor (PTGDR) and prostaglandin D2 synthetase (PTGDS) gene expression using short interfering RNA. US Patent Appl 20030148507 Fosnaugh K, et al. August 7, 2003

RNA interference. (review) Hannon GJ. Nature. 2002 Jul 11;418(6894):244-51

RNA interference: from an ancient mechanism to a state of the art therapeutic application? (review) Arenz C, et al Naturwissenschaften. 2003 Aug;90(8):345-59

RNA interference: gene silencing in the fast lane. (review) Kittler, et al Semin Cancer Biol. 2003 Aug;13(4):259-65

RNA interference: traveling in the cell and gaining functions? (review) Cerutti H. Trends Genet. 2003 Jan;19(1):39-46.

RNA-mediated gene regulation system: now and the future. (review) Yin JQ, et al Int J Mol Med. 2002 Oct;10(4):355-65

RNA-mediated gene silencing in non-pathogenic and pathogenic fungi. (review) De Backer MD, et al Curr Opin Microbiol. 2002 Jun;5(3):323-9

RNA-mediated interference as a tool for identifying drug targets. O'Neil NJ, et al Am J Pharmacogenomics. 2001;1(1):45-53

RNAi and related mechanisms and their potential use for therapy. (review) Agami R. Curr Opin Chem Biol. 2002 Dec;6(6):829-34

RNAi: an ever-growing puzzle. (review) Denli AM, et al Trends Biochem Sci. 2003 Apr;28(4):196-201

RNAi: gene-silencing in therapeutic intervention. (review) Shuey DJ, et al (Nucleonics) Drug Discov Today. 2002 Oct 15;7(20):1040-6.

Sequence, chemical, and structural variation of small interfering RNAs and short hairpin RNAs and the effect on mammalian gene silencing. Harborth J, et al Antisense Nucleic Acid Drug Dev. 2003 Apr;13(2):83-105

Silence of the strands: RNA interference in eukaryotic pathogens. (review) Cottrell TR, et al Trends Microbiol. 2003 Jan;11(1):37-43

siRNAs, ribozymes and RNA decoys in modeling stem cell-based gene therapy for HIV/AIDS. (review) Akkina R, et al Anticancer Res. 2003 May-Jun;23(3A):1997-2005

Small interfering RNAs and their chemical synthesis. Micura R. Angew Chem Int Ed Engl. 2002 Jul 2;41(13):2265-9

Synthesis and anti-influenza virus-A activity of circular dumbbell RNA DNA chimeric oligonucleotides. Abe T, et al Nucleic Acids Symp Ser. 1997;(37):219-20

The genetics of RNA silencing. (review) Tijsterman M, et al Annu Rev Genet. 2002;36:489-519

The microRNA world: small is mighty.. (review) Nelson P, et al Trends Biochem Sci. 2003 Oct;28(10):534-40

Thermodynamic studies on hairpin forming antisense-oligodeoxynucleotides directed against hepatitis C virus RNA. Lehmann TJ, et al Nucleosides Nucleotides. 1999 Jun-Jul;18(6-7):1689-91

Transcription factors as molecular targets: molecular mechanisms of decoy ODN and their design. (review) Tomita, et al Curr Drug Targets. 2003 Nov;4(8):603-8

Triplex-forming oligonucleotides: principles and applications. (review) Vasquez KM, et al Q Rev Biophys. 2002 Feb;35(1):89-107

Triple-helix forming oligonucleotides for targeted mutagenesis. US Patent Appl 20030232768 Glazer PM December 18, 2003

SBH)) Potent suppression of HIV type 1 infection by a short hairpin anti-CXCR4 siRNA. Anderson, et al AIDS Res Hum Retroviruses. 2003 Aug;19(8):699-706

Peptides : synthesis, structures, and applications. Eitor Gutte B (1995) San Diego : Academic Press, c1995

A Multimeric Synthetic Peptide Combinatorial Library. Wallace A, et al Pept Res. 1994 Jan-Feb;7(1):27-31

Branched building units for synthesizing cyclic peptides. US Patent 6,184,345 Reissmann, et al. February 6, 2001

Bromoacetylated synthetic peptides. Starting materials for cyclic peptides, peptomers, and peptide conjugates. (review) Robey FA Methods Mol Biol. 1994;35:73-90

Combinatorial libraries of substrate-bound cyclic organic compounds. US Patent 5,958,792 Desai, et al. September 28, 1999

Conjugation of epitope peptides with SH group to branched chain polymeric polypeptides via Cys(Npys). Mezo G, et al Bioconjug Chem. 2000 Jul-Aug;11(4):484-91

Contemporary Methods for Peptide and Protein Synthesis. (review) Saburo Aimoto Current Organic Chemistry 5(1) 2001

Cyclic polypeptides comprising a thioether linkage and methods for their preparation. US Patent 6,031,073 Yu February 29, 2000

Dimeric oligopeptide mixture sets. US Patent 6,287,787 Houghten, et al. September 11, 2001

Exploring privileged structures: the combinatorial synthesis of cyclic peptides. (review) Horton, et al J Comput Aided Mol Des. 2002 May-Jun;16(5-6):415-30

Functional mimicry of a discontinuous antigenic site by a designed synthetic peptide. Villen, et al Chembiochem. 2002 Mar 1;3(2-3):175-82

Multiple branch peptide construction. US Patent 6,379,679 Mabrouk, et al. April 30, 2002

Polypeptides that include conformation-constraining groups which flank a protein-protein interaction site.. US Patent 6,147,189 Evans, et al. November 14, 2000

Processes for coupling amino acids using bis-(trichloromethyl) carbonate. US Patent 6,512,092 Falb, et al. January 28, 2003

Synthesis and use of amino acid fluorides as peptide coupling reagents (see references herei US Patent 6,534,627 Carpino, et al. March 18, 2003

Synthesis of N-substituted oligomers. US Patent 5,977,301 Zuckerman, et al. November 2, 1999

Synthesis of Peptides by Solution. Methods. (review) Yoshio Okada Current Organic Chemistry 5(1) 2001

Libraries of backbone-cyclized peptidomimetics. US Patent 6,117,974 Gilon, et al. September 12, 2000

Generation and use of nonsupport-bound peptide and peptidomimetic combinatorial libraries. (review) Ostresh JM, et al Methods Enzymol. 1996;267:220

Peptide and peptidomimetic libraries. Molecular diversity and drug design. (review) al-Obeidi F, et al Mol Biotechnol. 1998 Jun;9(3):205-23. (review)

Combinatorial libraries by portioning and mixing. (review) Furka A, et al Comb Chem High Throughput Screen. 1999 Apr;2(2):105-22.

Photocleavable protecting groups and methods for their use. US Patent 6,566,515 McGall, et al. May 20, 2003

Polymer arrays. US Patent 6,346,413 Fodor, et al. February 12, 2002

Photocleavable agents and conjugates for the detection and isolation of biomolecules. US Patent 6,057,096 Rothschild, et al. May 2, 2000

Photolabile compounds and methods for their use. US Patent 5,917,016 Holmes June 29, 1999

Protocols for Oligonucleotide Conjugates: Synthesis and Analytical Techniques (Methods in Molecular Biology, Vol 26). Agrawal S (1993) Humana Press

Amphiphilic 3'-Peptidyl-RNA Conjugates. Terenzi, et al Angew Chem Int Ed Engl. 2003 Jun 30;42(25):2909-2912

An efficient and versatile synthesis of bisPNA-peptide conjugates based on chemoselective oxime formation. Neuner P, et al Bioconjug Chem. 2003 Mar-Apr;14(2):276-81

Automated synthesis of peptide nucleic acids and peptide nucleic acid-peptide conjugates. Mayfield LD, et al Anal Biochem. 1999 Mar 15;268(2):401-4

Bactericidal antisense effects of peptide-PNA conjugates. Good L, et al Nat Biotechnol. 2001 Apr;19(4):360-4

The functionalization of oligonucleotides via phosphoramidite derivatives. Beaucage SL, et al Tetrahedron (1993) 49, 1925­1963.

Bifunctional Reagents. (review) Ji TH, Meth. Enzymol. 91, 580-609 (1983)

Carbohydrate-directed cross-linking reagents. US Patent 6,124,435 Ashkenazi, et al. September 26, 2000

Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo. Pooga M, et al Nat Biotechnol. 1998 Sep;16(9):857-61

Cell permeabilization and uptake of antisense peptide-peptide nucleic acid (PNA) into Escherichia coli. Eriksson M, et al J Biol Chem. 2002 Mar 1;277(9):7144-7. Epub 2001 Dec 05

Chemical cross-linking of peptides derived from RecA with single-stranded oligonucleotides containing 5-formyl-2'-deoxyuridine. Sugiyama T, et al Nucleosides Nucleotides Nucleic Acids. 2001 Apr-Jul;20(4-7):1079-83

Chemoenzymatic synthesis and antibody detection of DNA glycoconjugates. Wang Y, et al Bioconjug Chem. 2003 Nov-Dec;14(6):1314-22

Compositions for inhibiting RNA activity. US Patent 5,514,786 Cook, et al. May 7, 1996

Conformatinally-restricted combinatorial library composition and method. WO9700267 HODGES, et al 1997-01-03

Conjugates and compositions for cellular delivery. US Patent Appl 20030130186 Vargeese C, et al. July 10, 2003

PN Peptide-mediated cellular delivery of antisense oligonucleotides and their analogues. (review) Gait MJ Cell Mol Life Sci. 2003 May;60(5):844-53

Conjugates and methods of forming conjugates of oligonucleotides and carbohydrates. US Patent 6,444,806 Veerapanani, et al. September 3, 2002

Conjugates of Oligonucleotides and Modified Oligonucleotides: A Review of Their Synthesis and Properties. Goodchild, et al Bioconjugate Chemistry, 1990, 1, 165

Derivatized oligonucleotides having improved uptake and other properties (see references herein). US Patent 6,395,492 Manoharan, et al. May 28, 2002

DNA-templated combinatorial library chemistry. WO0023458 HALPIN, et al 2000-04-27

Face-to-face and edge-to-face pi-pi interactions in a synthetic DNA hairpin with a stilbenediether linker. Egli M, et al J Am Chem Soc. 2003 Sep 10;125(36):10842-9

Synthesis of 5' oligonucleotide hydrazide derivatives and their use in preparation of enzyme-nucleic acid hybridization probes. Ghosh SS, et al Anal Biochem (1989) 178, 43­51

Rapid routes of synthesis of oligonucleotide conjugates from non-protected oligonucleotides and ligands possessing different nucleophilic or electrophilic functional groups. Grimm GN, et al Nucleosides Nucleotides Nucleic Acids (2000) 19, 1943­1965

Bioconjugate Techniques. Hermanson GT (1996) Academic Press San Diego CA

Highly efficient synthesis of peptide-oligonucleotide conjugates: chemoselective oxime and thiazolidine formation. Forget D, et al Chemistry. 2001 Sep 17;7(18):3976-84

Hybridization properties of oligodeoxynucleotide pairs bridged by polyarginine peptides. Wei, et al Nucleic Acids Res 1996 24(4):655-661

Immunostimulatory polynucleotide/immunomodulatory molecule conjugates. US Patent 6,610,661 Carson, et al. August 26, 2003

Incorporation of a non-nucleotide bridge into hairpin oligonucleotides capable of high-affinity binding to the Rev protein of HIV-1. Nelson JS, et al Biochemistry. 1996 Apr 23;35(16):5339-44

Ligands to enhance cellular uptake of biomolecules. {Carbohydrate-conjugated oligonucleotides} US Patent 5,994,517 Ts'o, et al. November 30, 1999

Linkage of proteins to nucleic acids. US Patent 4,587,044 Miller, et al. May 6, 1986

Methods and reagents for introducing a sulfhydryl group into the 5'-terminus of RNA. US Patent Appl 20030165849 Zhang B, et al. September 4, 2003

Methods for producing 5'-nucleic acid-protein conjugates. US Patent 6,623,926 Lohse, et al. September 23, 2003

Methods for the preparation of conjugated oligomers. US Patent 6,335,437 Manoharan January 1, 2002

Modified peptide nucleic acid (PNA) molecules. US Patent 6,548,651 Nielsen, et al. April 15, 2003

Modified phosphorous intermediates for providing functional groups on the 5' end of oligonucleotides. US Patent 5,786,512 Jones, et al. July 28, 1998

Multivalent macrolide antibiotics. US Patent 6,566,509 Griffin, et al. May 20, 2003

New reagents and methods for the synthesis of internal and 3'-labeled DNA. Lyttle MH, et al Bioconjug Chem. 2002 Sep-Oct;13(5):1146-54

Nucleic acid-peptide display libraries containing peptides with unnatural amino acid residues and methods of making same using peptide modifying agents. US Patent Appl 20030235852 Roberts RW, et al. December 25, 2003

Oligonucleotide sugar conjugate, method of producing oligonucleotide sugar conjugate. JP2001247596 KAZUKIYO, et al 2001-09-11

Oligonucleotide-folate conjugates. US Patent 6,528,631 Cook, et al. March 4, 2003

Oligonucleotide-polyamide conjugates and methods of production and applications of the same. US Patent 5,525,465 Haralambidis, et al. June 11, 1996

Oligonucleotide-polyamide conjugates. US Patent 5,677,440 Haralambidis, et al. October 14, 1997

Oligonucleotide-polyamine conjugates. WO8903849 HARALAMBIDIS JIM 1989-05-05

Oligonucleotides conjugated to protein-binding drugs. US Patent 6,656,730 Manoharan December 2, 2003

Oligonucleotides modified with conjugate groups. US Patent 6,172,208 Cook January 9, 2001

Parallel synthesis of PNA-peptide conjugate libraries. Awasthi SK, et al Comb Chem High Throughput Screen. 2002 May;5(3):253-9

Peptide acceptor ligation methods. WO 0107657 Kurz, M, et al (2001)

Peptide linkers for improved oligonucleotide delivery. US Patent 5,574,142 Meyer Jr, et al. November 12, 1996

Peptide nucleic acid conjugates. US Patent 6,180,767 Wickstrom, et al. January 30, 2001

Peptide-based nucleic acid mimics (PENAMS). US Patent 5,705,333 Shah, et al. January 6, 1998

Phosphate linked oligomers formed of monomeric diols and processes for preparing same. US Patent 6,448,373 Cook, et al. September 10, 2002

PNA and DNA conjugates and methods for preparation thereof. US Patent 6,197,513 Coull, et al. March 6, 2001

PNA combinatorial libraries and improved methods of synthesis. US Patent 5,831,014 Cook, et al. November 3, 1998

Preparation of oligonucleotide-biotin conjugates with cleavable linkers. Soukup GA, et al Bioconjug Chem. 1995 Jan-Feb;6(1):135-8

Process for preparing peptide derivatized oligomeric compounds (see references herei US Patent 6,559,279 Manoharan, et al. May 6, 2003

Process for preparing peptide derivatized oligomeric compounds. US Patent 6,559,279 Manoharan, et al. May 6, 2003

Protein carrier system for therapeutic oligonucleotides. US Patent Appl 20030166512 Xie, D September 4, 2003

RNA-antibody fusions and their selection. US Patent 6,518,018 Szostak, et al. February 11, 2003

Screening for Novel Antimicrobials from Encoded Combinatorial Libraries by Using a Two-Dimensional Agar Format. Silen, et al Antimicrob Agents Chemother. 1998 June; 42 (6): 1447­1453

Semisynthesis of proteins by expressed protein ligation. (review) Muir TW Annu Rev Biochem. 2003;72:249-89

Sequence-specific gene cleavage in intact mammalian cells by 125I-labeled triplex-forming oligonucleotides conjugated with nuclear localization signal peptide. Sedelnikova OA, et al Antisense Nucleic Acid Drug Dev. 2002 Feb;12(1):43-9

Site-specific transfection of eukaryotic cells using polypeptide-linked recombinant nucleic acid. US Patent 5,843,643 Ratner December 1, 1998

Solid-Phase synthesis of a dendritic peptide related to a retinoblastoma protein fragment utilizing a combined boc- and fmoc-chemistry approach. Cavallaro V, et al J Pept Sci. 2001 May;7(5):262-9

Synthesis of protein-nucleic acid conjugates by expressed protein ligation. Lovrinovic M, et al Chem Commun (Camb). 2003 Apr 7;(7):822-3

Synthesis of Ser-His-Gly.DNA conjugates. Li XQ, et al Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002 Jul;34(4):506-11

Synthesis, structure, and photochemistry of exceptionally stable synthetic DNA hairpins with stilbene diether linkers. Lewis FD, et al J Am Chem Soc. 2002 Oct 16;124(41):12165-73

The affinity of an oligodeoxynucleotide-peptide conjugate for an RNA hairpin loop depends on stereochemistry at the DNA-peptide junction. Sahasrabudhe PV, et al J Biomol Struct Dyn. 1996 Feb;13(4):585-91

Total stepwise solid-phase peptide-oligonucleotide conjugate synthesis on macroporous polystyrene. Stetsenko DA, et al Nucleosides Nucleotides Nucleic Acids. 2003 May-Aug;22(5-8):1379-82

Use of a ribozyme to join nucleic acids and peptides. US Patent 6,143,503 Baskerville, et al. November 7, 2000

Use of peptides-on-plasmids combinatorial library to identify high-affinity peptides that bind rhodopsin. Gilchrist A, et al Methods Enzymol. 2000;315:388-404

2'-modified nucleosides for site-specific labeling of oligonucleotides. Krider ES, et al Bioconjug Chem. 2002 Jan-Feb;13(1):155-62

A concise method for the preparation of peptide and arginine-rich peptide-conjugated antisense oligonucleotide. Chen CP, et al Bioconjug Chem. 2003 May-Jun;14(3):532-8

An efficient and versatile synthesis of bisPNA-peptide conjugates based on chemoselective oxime formation. Neuner P, et al Bioconjug Chem. 2003 Mar-Apr;14(2):276-81

Covalent protein-oligonucleotide conjugates for efficient delivery of antisense molecules. Rajur SB, et al Bioconjug Chem. 1997 Nov-Dec;8(6):935-40

Design of a targeted peptide nucleic acid prodrug to inhibit hepatic human microsomal triglyceride transfer protein expression in hepatocytes. Biessen EA, et al Bioconjug Chem. 2002 Mar-Apr;13(2):295-302

Direct, solid phase assembly of dihydropyrroloindole peptides with conjugated oligonucleotides. Lukhtanov EA, et al Bioconjug Chem. 1996 Sep-Oct;7(5):564-7

Incorporation of an aldehyde function in oligonucleotides. Tilquin JM, et al Bioconjug Chem. 2001 May-Jun;12(3):451-7

New reagents for the introduction of reactive functional groups into chemically synthesized DNA probes. Skrzypczynski Z, et al Bioconjug Chem. 2003 May-Jun;14(3):642-52

Oligonucleotide-polymer conjugates: effect of the method of synthesis on their structure and performance in diagnostic assays. Minard-Basquin C, et al Bioconjug Chem. 2000 Nov-Dec;11(6):795-804.

Peptide-oligonucleotide phosphorothioate conjugates with membrane translocation and nuclear localization properties. Antopolsky M, et al Bioconjug Chem. 1999 Jul-Aug;10(4):598-606

Preparation and applications of peptide-oligonucleotide conjugates. (review) Tung CH, et al Bioconjug Chem. 2000 Sep-Oct;11(5):605-18. (review) No abstract available

Preparation and evaluation of tumor-targeting peptide-oligonucleotide conjugates. Mier W, et al Bioconjug Chem. 2000 Nov-Dec;11(6):855-60

Preparation of conjugates of oligodeoxynucleotides and lipid structures and their interaction with low-density lipoprotein. Rump ET, et al Bioconjug Chem. 1998 May-Jun;9(3):341-9

Protamine-fragment peptides fused to an SV40 nuclear localization signal deliver oligonucleotides that produce antisense effects in prostate and bladder carcinoma cells. Benimetskaya L, et al Bioconjug Chem. 2002 Mar-Apr;13(2):177-87.

Signal peptide mimics conjugated to peptide nucleic acid: a promising solution for improving cell membrane permeability. Li X, et al Bioconjug Chem. 2003 Jan-Feb;14(1):153-7.

Synthesis and binding properties of oligonucleotides carrying nuclear localization sequences. de La Torre BG, et al Bioconjug Chem. 1999 Nov-Dec;10(6):1005-12.

Synthesis and characterization of a peptide nucleic acid conjugated to a D-peptide analog of insulin-like growth factor 1 for increased cellular uptake. Basu S, et al Bioconjug Chem. 1997 Jul-Aug;8(4):481-8

Synthesis of antisense oligonucleotide-peptide conjugate targeting to GLUT-1 in HepG-2 and MCF-7 Cells. Chen CP, et al Bioconjug Chem. 2002 May-Jun;13(3):525-9

Synthesis of antisense oligonucleotides conjugated to a multivalent carbohydrate cluster for cellular targeting. Maier MA, et al Bioconjug Chem. 2003 Jan-Feb;14(1):18-29

Synthesis of oligodeoxynucleotides containing N4-mercaptoethylcytosine and their use in the preparation of oligonucleotide-peptide conjugates carrying c-myc tag-sequence. Gottschling D, et al Bioconjug Chem. 1998 Nov-Dec;9(6):831-7

Synthesis of oligonucleotides containing 3'-alkylcarboxylic acids using a palladium labile oligonucleotide solid phase synthesis support. Matray TJ, et al Bioconjug Chem. 1997 Mar-Apr;8(2):99-102

Synthesis of radiometal-labeled and fluorescent cell-permeating peptide-PNA conjugates for targeting the bcl-2 proto-oncogene. Gallazzi F, et al Bioconjug Chem. 2003 Nov-Dec;14(6):1083-95

Tailored hydrophobic cavities in oligonucleotide-steroid conjugates. Letsinger RL, et al Bioconjug Chem. 1998 Nov-Dec;9(6):826-30

Use of Nalpha-Fmoc-cysteine(S-thiobutyl) derivatized oligodeoxynucleotides for the preparation of oligodeoxynucleotide-peptide hybrid molecules. Soukchareun S, et al Bioconjug Chem. 1998 Jul-Aug;9(4):466-75

Versatile linker chemistry for synthesis of 3'-modified DNA. Lyttle MH, et al Bioconjug Chem. 1997 Mar-Apr;8(2):193-8

General chemical ligation. US Patent 6,307,018 Kent, et al. October 23, 2001

Synthesis of peptide-oligonucleotide conjugates for chromium coordination. Civitello ER, et al Bioconjugate Chem 2001 12(4):459-463

Encoded combinatorial chemistry. Brenner S, et al Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5381-3

Encoded combinatorial chemical libraries. US Patent 6,060,596 Lerner, et al. May 9, 2000

Oligonucleotide tags for sorting and identification. US Patent 6,172,218 Brenner January 9, 2001

Detection of nucleic acid sequence differences using the ligase detection reaction with addressable arrays. US Patent 6,506,594 Barany, et al. January 14, 2003

Systems tools and methods of assaying biological materials using spatially-addressable arrays. US Patent 6,428,957 Delenstarr August 6, 2002

Addressable protein arrays. US Patent 6,537,749 Kuimelis, et al. March 25, 2003

Advancing molecular therapies through in vivo bioluminescent imaging. (review) McCaffrey A, et al Mol Imaging. 2003 Apr;2(2):75-86

Method and apparatus for performing large numbers of reactions using array assembly with releasable primers. US Patent 6,632,641 Brennan, et al. October 14, 2003

A method of forming neuraminidate inhibitors by dynamic combinatorial chemistry and compounds obtained. Heiko, et al WO03033437 2003-04-24

Drug discovery by dynamic combinatorial libraries. (review) Ramstrom O, et al Nat Rev Drug Discov. 2002 Jan;1(1):26-36

Generation of bis-cationic heterocyclic inhibitors of Bacillus subtilis HPr kinase/phosphatase from a ditopic dynamic combinatorial library. Bunyapaiboonsri T, et al J Med Chem. 2003 Dec 18;46(26):5803-11

In situ generation and screening of a dynamic combinatorial carbohydrate library against concanavalin A. Ramstrom O, et al Chembiochem. 2000 Jul 3;1(1):41-8

March's advanced organic chemistry : reactions, mechanisms, and structure (5th ed). Smith MB & March J (2001) New York : Wiley

Aptamers containing sequences of nucleic acid or nucleic acid analogues bound homologously, or in novel complexes. US Patent Appl 20030022853 Erikson GH, et al January 30, 2003

High affinity nucleic acid aptamers for streptavidin incorporated into bi-specific capture ligands. Tahiri-Alaoui, et al Nucleic Acids Res. 2002 May 15;30(10):e45

Hybridization characteristics of biomolecular adaptors, covalent DNA--streptavidin conjugates. Niemeyer CM, et al Bioconjug Chem. 1998 Mar-Apr;9(2):168-75

Long-range photoinduced electron transfer through a DNA helix. Murphy CJ, et al Science 1993 Nov 12;262(5136):1025-9.

Novel therapeutic binding molecule complexes. US Patent Appl 20030104045 Virtanen J, et al. June 5, 2003

Oligonucleotide conjugates. US Patent 5,391,723 Priest February 21, 1995

Longitude) Oligonucleotide-directed self-assembly of proteins: semisynthetic DNA--streptavidin hybrid molecules as connectors for the generation of macroscopic arrays and the construction of supramolecular bioconjugates. Niemeyer, et al Nucleic Acids Res. 1994 Dec 25;22(25):5530-9

Longitude) Targeted delivery of a therapeutic entity using complementary. US Patent 5,733,523 Kuijpers et al March 31, 1998

Longitude) The developments of semisynthetic DNA-protein conjugates. (review) Neimeyer CM Trends Biotechnol 2002 20(9):395-401

ChiMicroarrays Methods and Applications: Nuts & Bolts. Hardiman G (2003) DNA Press

ChiMicroarray Biochip Technology. Schena M (2000) Eaton Publishing Natick MA

Evaluation of single-stranded nucleic acids as carriers in the DNA-directed assembly of macromolecules. Niemeyer CM, et al J Biomol Struct Dyn. 1999 Dec;17(3):527-38

Combinatorial protein domains. US Patent Appl 20030078192 Winter GP, et al. April 24, 2003

Covalent dimer of kit ligand. US Patent 5,525,708 Nocka, et al. June 11, 1996

Pyranosyl-RNA supramolecules containing non-hydrogen-bonding base-pairs. Hamon C, et al Synlett (1999) 940­944

Method of making multispecific antibodies having heteromultimeric and common components. US Patent Appl 20030207346 Arathoon WR, et al November 6, 2003

Peptide design based on an antibody complementarity-determining region (CDR): construction of porphyrin-binding peptides and their affinity maturation by a combinatorial method. Takahashi M, et al Chemistry. 2000 Sep 1;6(17):3196-203

Sequence-selective nonmacrocyclic two-armed receptors for peptides. Nestler HP. Mol Divers. 1996 Oct;2(1-2):35-40.

Enhanced targeting specificity to tumor cells by simultaneous recognition of two antigens. Hillairet de Boisferon M, et al Bioconjug Chem. 2000 Jul-Aug;11(4):452-60.