Significant progress has been made toward discovery and development of anti-HIV agents acting at several critical stages of the viral life cycle. Despite the advances, clinical efficiency of inhibitors of HIV specific enzymes, reverse transcriptase (RT) and protease (P), remains to be improved in terms of cellular bio-availability, toxicities and cross HIV resistance. This proposal attempts to achieve these improvements by three drug conjugation methodologies. (1) Synthesis of an HIV-RT inhibitor, AZT, with steroid antidrugs. This could increase the inhibitor's lipophilicity, permeability into cell and half life. The steroid moiety upon breakage of the conjugate should be free of systemic side effects. (2) Preparation of AZT conjugates with steroidal phophotriesters. They could achieve the bio-availability advantages as well as a more activated drug form upon breakage of the conjugate. (3) Conjugation of AZT and a potent HIV-P inhibitor, a cyclic urea. This could not only imp rove cellular bioavailability, reduce toxicities, but also diminish the cross resistance by releasing a HIV-RT and a HIV-P inhibitor, achieving a synergistic effect. Results of these investigations will yield insight into the structural characteristics of conjugates with a promise of providing a rational basis for the development of more efficient anti-HIV agents.
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