HIV TRIALS

艾滋病毒试验

• 批准号: 2464463
• 负责人: H MITSUYA
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2464463
• 关键词: 2'3' dideoxycytidine; 2'3' dideoxyinosine; AIDS therapy; HIV infections; antiAIDS agent; antiviral agents; clinical research; clinical trials; combination cancer therapy; enzyme inhibitors; gene mutation; human immunodeficiency virus 1; human subject; human therapy evaluation; hydroxyurea; lymphocyte; monocyte; multidrug resistance; phytohemagglutinins; protease inhibitor; reverse transcriptase inhibitors; ribonucleotide reductase; virus load; zidovudine

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.

作为开发新型抗病毒化合物的努力，我们正在开发 过渡态模拟三肽HIV蛋白酶抑制剂KNI-272 含有别苯基降甲他汀[Apns;（2S，3S）-3-氨基-2-羟基-4-苯基- 丁酸]。 KNI-272首次用于晚期乳腺癌患者， 1994年3月在医药分支感染HIV-1。 我们现已发现 在蛋白酶编码区发生的某些突变 在体外赋予HIV-1对KNI 272的抗性。 我们最近有更多的 鉴定了几种具有活性的含Apns的蛋白酶抑制剂 抗野生型HIV-1和抗KNI-272的HIV-1变体。 越来越多的数据表明，HIV-1变异体的发展与 对逆转录酶（RT）抑制剂的敏感性降低与 接受联合治疗的患者的临床恶化 多种RT抑制剂（例如，AZT/ddC和AZT/ddI）。 在这方面我们 已经鉴定了一组新的突变[Ala-62瓦尔（A62 V），V75 I，F77 L， F116 Y和Q151 M]，其赋予 病毒对多种抗逆转录病毒药物的敏感性降低 双脱氧核苷（ddNs）。我们最近定义了病毒学和 这些突变的酶性质。 在我们研究的另一个领域， 核苷RT抑制剂，我们已经证明了差异抗HIV-1 植物血凝素激活外周血中ddNs活性 单核细胞（PHA-PBM）和静息PBM。 我们还发现 羟基脲（HU）可增强ddN抗病毒活性，特别是 通过抑制脱氧核糖核苷酸还原酶而抑制ddI。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，这可能会开辟一条新的途径， 设计艾滋病的联合化疗。