OLIGONUCLEOTIDE ANALOGS AS ANTIVIRAL/ANTICANCER AGENTS

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This Program Project has only one objective -- the development and application of nonionic deoxyoligonucleotide analogs as probes in scientific studies and as antivirus/anticancer therapeutic agents. The only difference between this analog and the deoxyoligonucleotide is that the backbone of the analog consists of the nonionic methylphosphonate linkage instead of the negative phosphodiester linkage. These analogs are totally resistant to nucleases; are taken up by mammalian cells; from stable, sequence-specific duplexes with complementary single-stranded regions of RNA; and selectively inhibit the function and splicing of targeted mRNA in cells. These analogs thus serve as specific "masking tape" for specific gene expression, termed as "Matagen". Previous studies show sequence-specific Matagens specifically inhibit globin synthesis in reticulocytes, Vesicular stomatitis virus replication and viral protein synthesis in mouse L cells, and SV-40 large T antigen synthesis in monkey cells, as well as Herpes simplex virus replication and expression of immediate early genes in Vero or human cells. Thus, these Matagens can inhibit viral replication without affecting the host cells. The Matagens will be modified with a terminal attachment of psoralen and such modifed Matagens can crosslink with the targeted RNA in duplex formation and upon near UV irradiation. Matagens will also be modified with a terminal attachment of a Fe++-chelating group (such as EDTA), which allows the generation of oxygen free radicals in a redox reaction. The Matagen-EDTA can therefore cleave the backbone of the targeted mRNA upon formation of a duplex. This Program Project consists of a Chemistry Group headed by Dr. Paul S. Miller at John Hopkins; a Pharmacology/Toxicity Group headed by Dr. Michael Colvin at Johns Hopkins; a Herpes Simplex Virus Group headed by Dr. Laure Aurelian at the University of Maryland Medical School; a Human T-Cell Leukemia Virus III (HTLV-III) Group, headed by Dr. Jeffrey Laurence at the Cornell Medical center; an Oncogene Group headed by Dr. Esther Chang of the Uniformed Services University, and a Molecular Cytology Group headed by Dr. Paul O.P. Ts'o, who also serves as the Principal Investigator. The Scientific Core Project is headed by Dr. Paul Miller, who will also serve as Co-Principal Investigator. Matagen will be provided as specific suppressors of viral gene function of the following viruses: HSV-2, cytomegalovirus (CMV); SV-40; HTLV-III; as well as oncogenes in animal tumor models and in Syrian hamster embryo cells. This study is intended to prepare for the clinical trial of Matagen in the near future.