AMPHIPHILIC OLIGONUCLEOTIDE CONJUGATES

THE EFFECTIVE SYNTHESIS AND USE OF ENZYMATICALLY STABLE OLIGONUCLEOTIDE ETHYLTRIESTERS AND METHYLPHOSPHONATES IN SELECTIVELY INHIBITING PROTEIN SYNTHESIS IN CULTURED CELLS HAS BEEN DEMONSTRATED. RELATIVELY HIGH EXTERNAL CONCENTRATIONS ARE REQUIRED FOR EFFECTIVE PROTEIN SYNTHESIS INHIBITION DUE IN PART TO LIMITED CELL PENETRATION OF SOME DERIVATIVES. IT IS PROPOSED TO DEVELOP THE USE OF HIGHLY SOLUBLE, CELL-PENETRATING, AMPHIPHILIC OLIGONUCLEOTIDE CONJUGATES, WHICH INITIAL EXPERIMENTS SHOW TO BE 10 TIMES MORE EFFECTIVE THAN NONCONJUGATED OLIGOMERS. THE GOAL IS TOPRODUCE EFFECTIVE ANTISENSE OLIGONUCLEOTIDES WITH SIGNIFICANT ANTIVIRAL ACTIVITY. IN PHASE I, POLYETHYLENE GLYCOL CONJUGATES OF NORMAL AND METHYLPHOSPHONATE DNA WILL BE SYNTHESIZED AND PURIFIED, AND THEIR ABILITY TO SELECTIVELY INHIBIT HEMOGLOBIN SYNTHESIS IN CULTURED MOUSE CELLS WILL BE COMPARED. IN PHASE II, IT IS PLANNED TO CONSTRUCT AND TEST THE OPTIMIZED CONJUGATES FOR THEIR ABILITY TO INHIBIT THE GROWTH OF HIV IN CULTURED CELLS. THIS WORK WILL THEN BE EXTENDED TO ANIMAL TOXICITY AND PHARMACOLOGIC STUDIES TO BRING THESE COMPOUNDS TO THE INVESTIGATIONAL NEW DRUG STAGE FOR TESTING IN HUMANS.