Morpholino antisense oligomers: design, preparation, and properties.

Antisense promised major advances in treating a broad range of intractable diseases, but in recent years progress has been stymied by technical problems, most notably inadequate specificity, ineffective delivery into the proper subcellular compartment, and unpredictable activity within cells. Herein is an overview of the design, preparation, and properties of Morpholino oligos, a novel antisense structural type that solves the sequence specificity problem and provides high and predictable activity in cells. Morpholino oligos also exhibit little or no nonantisense activity, afford good water solubility, are immune to nucleases, and are designed to have low production costs.

[1]  J. Summerton,et al.  Morpholino and phosphorothioate antisense oligomers compared in cell-free and in-cell systems. , 1997, Antisense & nucleic acid drug development.

[2]  J. Paulauskis,et al.  In Vitro Efficacy of Morpholino-modified Antisense Oligomers Directed against Tumor Necrosis Factor-α mRNA* , 1996, The Journal of Biological Chemistry.

[3]  J. Summerton,et al.  A simple method for delivering morpholino antisense oligos into the cytoplasm of cells. , 1996, Antisense & nucleic acid drug development.

[4]  D. Barofsky,et al.  Resistance of morpholino phosphorodiamidate oligomers to enzymatic degradation. , 1996, Antisense & nucleic acid drug development.

[5]  J. Bisi,et al.  An assessment of the antisense properties of RNase H-competent and steric-blocking oligomers. , 1995, Nucleic acids research.

[6]  A. Krieg,et al.  Phosphorothioate oligodeoxynucleotides: antisense or anti-protein? , 1995, Antisense research and development.

[7]  C. Stein,et al.  Patterns of intracellular compartmentalization, trafficking and acidification of 5'-fluorescein labeled phosphodiester and phosphorothioate oligodeoxynucleotides in HL60 cells. , 1994, Nucleic acids research.

[8]  S. Kanaya.  [Ribonuclease H]. , 1994, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[9]  Y. Cheng,et al.  Antisense oligonucleotides as therapeutic agents--is the bullet really magical? , 1993, Science.

[10]  B. Froehler,et al.  Antisense gene inhibition by oligonucleotides containing C-5 propyne pyrimidines. , 1993, Science.

[11]  B. Sproat,et al.  Comparative evaluation of seven oligonucleotide analogues as potential antisense agents. , 1993, Journal of medicinal chemistry.

[12]  J. Toulmé,et al.  RNase H-mediated inhibition of translation by antisense oligodeoxyribonucleotides: use of backbone modification to improve specificity. , 1992, Gene.

[13]  W. C. Johnson,et al.  Stacking interactions of ApA analogues with modified backbones , 1992, Biopolymers.

[14]  J. Nelson,et al.  Acyclic Nucleic Acid Analogues: Synthesis and Oligomerization of . gamma.,4-Diamino-2-oxo-1(2H)-pyrimidinepentanoic Acid and δ,4- Diamino-2-oxo-1(2H)-pyrimidinehexanoic Acid. , 1992 .

[15]  E. Wagner,et al.  Effective incorporation of 2'-O-methyl-oligoribonucleotides into liposomes and enhanced cell association through modification with thiocholesterol. , 1992, Nucleic acids research.

[16]  Peter E. Nielsen,et al.  Peptide nucleic acids (PNA) : oligonucleotide analogues with an achiral peptide backbone , 1992 .

[17]  J. S. Cohen,et al.  Oligodeoxynucleotides as antisense inhibitors of gene expression. , 1992, Progress in nucleic acid research and molecular biology.

[18]  A. Periasamy,et al.  Mechanism of cellular uptake of modified oligodeoxynucleotides containing methylphosphonate linkages. , 1991, Nucleic acids research.

[19]  D. Ecker,et al.  Effects of phosphorothioate capping on antisense oligonucleotide stability, hybridization and antiviral efficacy versus herpes simplex virus infection. , 1991, Nucleic acids research.

[20]  J. Nelson,et al.  Acyclic nucleic acid analogs: synthesis and oligomerization of .gamma.,4-diamino-2-oxo-1(2H)-pyrimidinepentanoic acid and .delta.,4-diamino-2-oxo-1(2H)-pyrimidinehexanoic acid , 1991 .

[21]  W. Olson,et al.  Molecular Modeling of Acyclic Polyamide Oligonucleotide Analogues , 1991 .

[22]  J. Summerton,et al.  Uncharged stereoregular nucleic acid analogs: 2. Morpholino nucleoside oligomers with carbamate internucleoside linkages. , 1989, Nucleic acids research.

[23]  J. Toulmé,et al.  Comparative inhibition of rabbit globin mRNA translation by modified antisense oligodeoxynucleotides. , 1989, Nucleic acids research.

[24]  N. Yamamoto,et al.  Inhibition of human immunodeficiency virus (HIV-1) replication by synthetic oligo-RNA derivatives. , 1989, Nucleic acids research.

[25]  J. S. Cohen,et al.  Phosphorothioate Oligodeoxynucleotide Analogues , 1989 .

[26]  P. Miller.  Non-ionic Antisense Oligonucleotides , 1989 .

[27]  J. Walder,et al.  Role of RNase H in hybrid-arrested translation by antisense oligonucleotides. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[28]  B. Froehler,et al.  Phosphoramidate analogues of DNA: synthesis and thermal stability of heteroduplexes. , 1988, Nucleic acids research.

[29]  J. Summerton,et al.  Uncharged stereoregular nucleic acid analogs. 1. Synthesis of a cytosine-containing oligomer with carbamate internucleoside linkages , 1987 .

[30]  J. Toulmé,et al.  Enzymatic amplification of translation inhibition of rabbit beta-globin mRNA mediated by anti-messenger oligodeoxynucleotides covalently linked to intercalating agents. , 1987, Nucleic acids research.

[31]  J. Summerton.  Intracellular inactivation of specific nucleotide sequences: a general approach to the treatment of viral diseases and virally-mediated cancers. , 1979, Journal of theoretical biology.

[32]  J. Summerton.  Sequence-specific crosslinking agents for nucleic acids: design and functional group testing. , 1979, Journal of theoretical biology.

[33]  J. Summerton,et al.  Sequence-specific crosslinking agents for nucleic acids. Use of 6-bromo-5,5-dimethoxyhexanohydrazide for crosslinking cytidine to guanosine and crosslinking RNA to complementary sequences of DNA. , 1978, Journal of molecular biology.

[34]  M. Stephenson,et al.  Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[35]  V. Zarytova,et al.  Synthesis of ribonucleosides and diribonucleoside phosphates containing 2-chloroethylamine and nitrogen mustard residues. , 1967, Tetrahedron letters.