MICHELLAMINE B ANALOGS FOR TREATMENT OF HIV INFECTION

描述：(改编自申请者摘要)更有效 需要开发治疗人类感染的疗法 导致获得性肺炎大流行的免疫缺陷病毒(HIV) 免疫缺陷综合征(艾滋病)。目前，艾滋病毒感染者可以 仅限量使用临床上可用的抗艾滋病毒药物进行治疗 一段时间，因为它们的毒副作用和 艾滋病毒对这些药物产生抗药性。这个 二(萘基四氢异喹啉)生物碱，胶束胺B是一种新的 治疗这种疾病的候选药物。这很自然 该产品不仅能抑制HIV-1和HIV-2在人体内的复制 T淋巴细胞在细胞培养中也能抑制HIV-1的复制 对目前可用的抗HIV核苷具有抗药性的菌株 毒品。由于米歇拉明B在细胞培养中具有抗HIV活性 以及它在两个动物模型中的低毒性，国家癌症研究所 目前正在进行药理学和毒理学研究 为第一阶段临床试验做准备。申请者提出了一个 米歇拉明B类似物的构效关系研究 抗病毒活性所需的药理活性基团及其最适 空间定向。然后，这些信息将允许设计和 合成比合成更容易获得的类似物 米海拉明B和有较有利的治疗指标。此外, 对这些类比的评估应提供有关 胶束胺抗病毒作用机制的研究。的两个类比 米歇尔胺B设计合成的初步研究抑制 HIV-1(HTLV-IIIB株)对人的细胞病变效应 淋巴母细胞系CEM-SS。两种类似物均可抑制重组HIV 逆转录酶，这表明抑制该酶可能 是其抗艾滋病毒活性的机制之一。两者也都被禁止了 蛋白激酶C的活性，因此，抑制蛋白激酶C 一种基本病毒蛋白的磷酸化可能是另一种机制 行动的一部分。

DESCRIPTION: (Adapted from Applicant's Abstract) More effective therapies need to be developed to treat infections by human immunodeficiency virus (HIV), which has caused the pandemic of acquired immune deficiency syndrome (AIDS). At present, HIV-infected patients can be treated with the clinically available anti-HIV drugs for only limited periods of time because of their toxic side effects and the ability of HIV to develop resistance to these drugs. The bis(naphthalenyltetrahydroisoquinoline) alkaloid, michellamine B is a new therapeutic candidate for the treatment of this disease. This natural product not only inhibits the replication of HIV types 1 and 2 in human T lymphocytes in cell culture but also inhibits the replication of HIV-1 strains that are resistant to the currently available anti-HIV nucleoside drugs. Because of the anti-HIV activity of michellamine B in cell culture and its low toxicity in two animal models, the National Cancer Institute is currently conducting pharmacological and toxicological studies in preparation for Phase 1 clinical trials. The applicants propose a structure-activity study on analogs of michellamine B to determine the pharmacophoric groups required for antiviral activity and their optimal spatial orientation. This information will then permit the design and synthesis of analogs that are more synthetically accessible than michellamine B and have a more favorable therapeutic index. In addition, evaluation of these analogs should provide valuable information on the mechanism of antiviral action of the michellamines. The two analogs of michellamine B designed and synthesized in preliminary studies inhibited the cytopathic effect of HIV- 1 (HTLV-IIIB strain) in the human lymphoblastoid cell line CEM-SS. Both analogs inhibited recombinant HIV reverse transcriptase, an indication that inhibition of this enzyme may be one of the mechanisms for their anti-HIV activity. Both also inhibited the activity of protein kinase C. Therefore, inhibition of the phosphorylation of an essential viral protein may be another mechanism of action.