CONJUGATES OF INHIBITORS OF HIV SPECIFIC ENZYMES W/ STEROID DERIVATIVES

在探索和发现方面取得了重大进展， 开发在几个关键阶段起作用的抗HIV药物， 病毒的生命周期 尽管取得了进展， HIV特异性酶、逆转录酶（RT）和 蛋白酶（P），在细胞方面仍有待改进 生物利用度、毒性和交叉HIV耐药性。 这项建议 试图通过三种药物缀合来实现这些改善 方法论。 (1)合成HIV-RT抑制剂AZT， 类固醇抗药物。 这可以增加抑制剂的亲脂性， 对细胞的渗透性和半衰期。 类固醇部分， 缀合物的断裂应该没有全身副作用。 (2)AZT与甾体磷酸三酯缀合物的制备。 他们可以实现生物利用度的优势，以及更多的 在缀合物断裂时活化的药物形式。 (3)缀合 AZT和一种有效的HIV-P抑制剂环脲 这不可能 不仅提高细胞生物利用度，降低毒性，而且 通过释放HIV-RT和HIV-P减少交叉耐药性 抑制剂，实现协同效应。 结果进行 调查将深入了解结构特征 的共轭与承诺提供一个合理的基础， 开发更有效的抗艾滋病毒药物。

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.