HIV TRIALS

作为开发新型抗病毒化合物的努力，我们正在开发 过渡状态模拟三肽HIV蛋白酶抑制剂KNI-272 含去甲肾上腺素[APNS；(2S，3S)-3-氨基-2-羟基-4-苯基- 丁酸]。KNI-272首先用于晚期糖尿病患者 1994年3月在医学处感染艾滋病毒-1。我们现在已经找到了 发生在蛋白酶编码区的某些突变可以 探讨HIV-1对KNI272的体外耐药性。我们最近有了更多 鉴定了几种活性的含APN的蛋白酶抑制剂 对抗野生型HIV-1和对KNI-272耐药的HIV-1变异体。 越来越多的数据表明，HIV-1变种的发展与 逆转录酶(RT)抑制剂敏感性降低与此有关 对接受联合治疗的患者的临床恶化 多种逆转录酶抑制剂(如AZT/ddC和AZT/ddi)。在这方面，我们 发现了一组新的突变[ALA-62Val(A62V)，V75I，F77L， F116Y和Q151M]在HIV-1 RT的聚合酶区域，这赋予了 对病毒的多种抗逆转录病毒敏感性降低 二脱氧核苷(DDNS)。我们最近定义了病毒学和 这类突变的酶特性。 在我们优化抗病毒活性的另一个研究领域 在核苷逆转录酶抑制剂中，我们已经证明了不同的抗HIV-1 植物血凝素激活的外周血中DDNS的活性 单个核细胞(PHA-PBM)和静息PBM。我们还发现， 羟基脲(HU)能增强DDNS的抗病毒活性，尤其是 Ddi通过抑制脱氧核糖核苷酸还原酶发挥作用。这些 数据表明，某些细胞酶的修饰可能会增强 抗HIV-1药物的抗病毒活性，这可能开辟一条新的途径 设计艾滋病的联合化疗方案。

As an effort to develop novel antiviral compounds, we are developing KNI-272, a transition-state mimetic tripeptide HIV protease inhibitor containing allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenyl- butyric acid]. KNI-272 was first administered to patients with advanced HIV-1 infection at the Medicine Branch in March 1994. We have now found that certain mutations occurring in the protease-encoding region can confer on HIV-1 resistance to KNI 272 in vitro. We have more recently identified several Apns-containing protease inhibitors which are active against both wild-type HIV-1 and HIV-1 variants resistant to KNI-272. The accumulating data suggest that the development of HIV-1 variants with reduced susceptibility to reverse transcriptase (RT) inhibitors is related to clinical deterioration in patients receiving combination therapy with multiple RT inhibitors (e.g., AZT/ddC and AZT/ddI). In this regard, we have identified a set of novel mutations [Ala-62 Val(A62V), V75I, F77L, F116Y, and Q151M] in the polymerase domain of RT of HIV-1, which confers on the virus a reduced sensitivity to multiple antiretroviral dideoxynucleosides (ddNs). We have recently defined virological and enzymatic properties of such mutations. In another area of our research efforts to optimize the antiviral activity of nucleoside RT inhibitors, we have demonstrated differential anti-HIV-1 activity of ddNs in phytohemagglutinin-activated peripheral blood mononuclear cells (PHA-PBM) and resting PBM. We have also found that hydroxyurea (HU) can potentiate antiviral activity of ddNs, particularly that of ddI, through inhibition of deoxyribonucleotide reductase. These data suggest that modification of certain cellular enzymes may enhance the antiviral activity of anti-HIV-1 drugs, which may open a new avenue in designing combination chemotherapy of AIDS.