Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1992-06-22
1996-04-02
Jones, W. Gary
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 15, C12Q 168, C12Q 100
Patent
active
055039758
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
This invention relates to synthetic oligomers of unique three-dimensional structure that combine the principles of polymer, peptide and synthetic DNA chemistry to provide rationally designed drugs, drug delivery systems, research tools and other products.
The invention also relates to unique oligonucleotide molecules in which 5-fluorodeoxycytidine inhibits DNA methyltrnasferase.
BACKGROUND OF THE INVENTION
Various heteropolymers are known (see, e.g., Seela, F. and Kaiser, K., Oligodeoxyribonucleotides containing 1,3-propanediol as a nucleoside substitute, Nucleic Acids Res. 15:3113-3129 (1987) and Connolly, B. A., The Synthesis of Oligonucleotides containing a primary amino group at the 5'-terminus, Nucleic Acids Res. 15:3131-3139 (1987)) and one example of a heterodimer exists. See Lemaitre, M., Bayard, B., and Leblue, B., Specific Antiviral Activity of a Poly(L-lysine)-Conjugated Oligodeoxyribonucleotide Sequence Complementary to Vesicular Stomatitis N Protein mRNA Initiation Site, Proc. Nat. Acad. Sci. U.S.A. 84:648-652 (1987). However, there is no known disclosure of molecules comprising linked heterologous blocks conforming to a predetermined or predictable three-dimensional structure.
Definitions
The following definitions apply to terms used in this specification and in the claims:
Block--An oligomer component of at least about 5 monomers, e.g., carbon atoms, amino acid residues or nucleotides which has an intrinsic tendency to self-associate inter se or with another block.
Unit--An oligomer component consisting of at least three blocks.
Oligomer--A molecule having from about 12 to about 150 monomers, e.g., carbon atoms, amino acid residues or nucleotides and comprising at least one unit.
Self-Association--The capability shared by two or more blocks to form a mutual linkage, e.g., the capability of homologous nucleic acid sequences to hybridize and of certain peptides to interact.
Homologous Block--One of a series of blocks where members of the series exhibit common properties, for example, one of a series of nucleic acid, peptide or organic polymer blocks. Organic polymer blocks may generally comprise straight or branched chain polyolefins such as polyethylene, polypropylene or polystyrene and other kinds of polymers which are not cross-linked.
Heterologous Block--One of a series of blocks whose members do not exhibit common properties.
Heterologous Block Oligomer (HBO)--An oligomer comprising at least one unit of the schematic formula A.sub.1 -B-A.sub.2 in which the block B is heterologous with respect to at least one of the blocks A.sub.1 and A.sub.2 and is constrained into a generally looped configuration by the self-association energy of the blocks A.sub.1 and A.sub.2 or in which the blocks A.sub.1 and A.sub.2 are heterologous and are constrained into a spatially juxtaposed position by the internal self-association of the block B.
SUMMARY OF THE INVENTION
HBO's provide a broad spectrum of novel molecules. The new molecules may be predesigned to achieve objectives which have been realized, with some difficulty, if at all.
HBO detergents can be formed with self-associated DNA blocks joined by simple linker blocks. The properties of these detergent molecules can be exploited in several ways. Micelles formed primarily of the self-associated DNA blocks may permit the passage of any short, double-stranded DNA through the bloodstream. Antisense molecules and short duplex DNA's more intrinsically resistant to DNase could be delivered in this fashion. "Suicide" substrates of duplex DNAs can be constructed to target tissues and neoplastic or virus infected cells. The inclusion of a hydrophobic linker block in these HBOs facilitates diffusion or transport across cell membranes at the requisite site.
A variety of applications in protein purification, for example, hydrophobic interaction chromatography are apparent. More specifically the biospecificity of DNA sequences may combine with the capacity of the linker block to interact with such a chromatographic column.
Both 5-fluorod
REFERENCES:
Websters Dictionary II, Riverside Publ. Co. (1984) p. 589.
Jones et al., Cell 20:85-93 (1980) "Cellular Differentiation, cytidine analogs . . . ".
Osterman et al., Biochemistry 27:5204-5210 (1988) "5-fluorocytosine in DNA is a mehanism-based . . . ".
Jones, Cancer Res. 46:461-466 (1986) "DNA Methylation and Cancer".
Lewis, Science 237:1570 (1987) "What does homology mean . . . ".
Call, et al., "Studies of mutagenicity and clastogenicity of 5-azacytidine in human lyphoblasts and Salmonella typhimurium" Mutation Research 160:249-257 (1986).
Kaysen, et al., "Incorporation of 5-Fluorodeoxycytidine and Metabolites into Nucleic Acids of Human MCF-7 Breast Carcinoma Cells", Cancer Research 46:4534-4538 (1986).
Carr, et al., "The tumorigenicity of 5-azacytidine in the male Fischer rat", Carcinogenesis 5:158301590 (1984).
Hori, T. A. "Induction of chromosome decondensation, siter-chromatid exchanges and endoreduplications by 5-azacytidine, an inhibitor of DNA methylation", Mutation Research 121:47-52 (1983).
Schmid, et al., "A direct demonstration of somatically paired heterochromatin of human chromosomes", Cytogenet. Cell Genet. 36:554-561 (1983).
Kaplan Bruce E.
Smith Steven S.
Campbell Eggerton
City of Hope
Irons Edward S.
Jones W. Gary
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