NUCLEAR TARGETING OF OLIGONUCLEOTIDE-PEPTIDE CONJUGATES

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, 16 PEPTIDE SEQUENCES WITH NUCLEAR TARGETING PROPERTIES HAVE BEEN IDENTIFIED. THREE OF THESE PEPTIDES WILL BE SYNTHESIZED AND CONJUGATED TO ANTISENSE OLIGODEOXYNUCLEOTIDES THAT INTERFERE WITH SURFACE ANTIGEN PRODUCTION IN HEPATITIS B VIRUS. EACH PEPTIDE-OLIGONUCLEOTIDE CONJUGATE WILL BE LABELED WITH RADIOACTIVE PHOSPHORUS AND TESTED FOR ITS ABILITY TO LOCALIZE TO THE NUCLEUS IN A CELL-FREE PREPARATION OF RAT LIVER NUCLEI. UNMODIFIED OLIGONUCLEOTIDES OF VARIOUS LENGTHS WILL ALSO BE RADIOLABELED, AND THEIR RATE OF NUCLEARUPTAKE/DIFFUSION WILL BE EVALUATED. THE PEPTIDE-OLIGONUCLEOTIDE CONJUGATES WILL ALSO BE EXAMINED FOR IMPROVED ANTISENSE EFFECT IN HEPATITIS B-INFECTED (HEP3B) CELLS. THESE EXPERIMENTS WILL CONSTITUTE A FEASIBILITY STUDY FOR THE DEVELOPMENT OF PEPTIDE-OLIGONUCLEOTIDE CONJUGATES THAT COULD BE IMPORTANT FOR THE THERAPEUTIC TREATMENT OF DISEASESCAUSED BY INFECTION WITH HUMAN IMMUNODEFICIENCY VIRUS, HEPATITIS B, HERPES VIRUSES, OR OTHER VIRUSES.