This Phase I study will explore the therapeutic possibilities of antisense oligodeoxynucleotides that have been covalently conjugated to signal peptides that can direct the transport of proteins into the nucleus. In recent years, sixteen peptide sequences with nuclear targeting properties have been identified. Each of these peptides will be synthesized and labeled with Texas Red or radioactive iodine. EAch labeled peptide will be tested for its ability to localize to the nucleus in cultured human foreskin-fibroblasts. those peptides having nuclear localization activity will be conjugated with an antisense oligodeoxynucleotides, labeled with acridine or radioactive phosphorous, that is complementary to the splice acceptor junction of the immediate early pre-mRNAs 4 and 5 of Herpes simplex virus I (HSV-1). By applying these double-labeled conjugates to cultured cells, """"""""active"""""""" peptides will be identified that are capable of delivering the linked oligodeoxynucleotide to the nucleus. Finally, antisense oligodeoxynucleotides conjugated to """"""""active"""""""" peptides will be compared with their non-conjugated analogues for their ability to interfere with Herpes simplex infection of cultured human foreskin fibroblast cells. These experiments will constitute a feasibility study for the development of peptide-oligodeoxynucleotide conjugates that could be important for the therapeutic treatment of diseases caused by infection with Human Immunodeficiency Virus, Herpes viruses, or other viruses.
|Reed, M W; Fraga, D; Schwartz, D E et al. (1995) Synthesis and evaluation of nuclear targeting peptide-antisense oligodeoxynucleotide conjugates. Bioconjug Chem 6:101-8|
|Hinrichsen, R D; Fraga, D; Reed, M W (1992) 3'-modified antisense oligodeoxyribonucleotides complementary to calmodulin mRNA alter behavioral responses in Paramecium. Proc Natl Acad Sci U S A 89:8601-5|
|Reed, M W; Adams, A D; Nelson, J S et al. (1991) Acridine- and cholesterol-derivatized solid supports for improved synthesis of 3'-modified oligonucleotides. Bioconjug Chem 2:217-25|