Rational design of drugs that induce human immunodeficiency virus replication
Rational design of drugs that induce human immunodeficiency virus replication
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DOI：
10.1128/jvi.77.19.10227-10236.2003
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发表时间：
2003-10-01
影响因子：
5.4
通讯作者：
Marquez, VE
中科院分区：
文献类型：
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作者：
Hamer, DH;Bocklandt, S;Marquez, VE
诱导人类免疫缺陷病毒1型（HIV-1）复制的药物可与高效抗逆转录病毒疗法（HAART）联合使用，以减少潜伏库的大小，这在一定程度上是病毒持续存在的原因。蛋白激酶C（PKC）是此类药物的合理靶点，因为它通过多种机制激活HIV-1转录。在这里，我们表明，HIV-1基因的表达可以诱导的有效的合成类似物的脂质第二信使二酰基甘油（DAG）合成的五元环平台上，降低了熵的结合相对于更灵活的DAG模板。通过改变这些合成DAG内酯的烷基侧链，可以最大化它们的效力和能力，使潜伏感染的T细胞对抗HIV-1免疫毒素的杀伤敏感，同时最小化CD 4和CXCR 4下调和肿瘤坏死因子α上调的副作用。两个先导化合物LMC 03和LMC 07调节一系列参与T细胞活化的PKC敏感基因，并诱导HIV-1感染者外周血单核细胞中的病毒基因表达。这些研究证明了合理设计药物的潜力，结合HAART和HIV特异性毒素，可用于通过强制病毒表达来减少或消除潜伏感染的储库。
Drugs that induce human immunodeficiency virus type 1 (HIV-1) replication could be used in combination with highly active antiretroviral therapy (HAART) to reduce the size of the latent reservoir that is in part responsible for viral persistence. Protein kinase C (PKC) is a logical target for such drugs because it activates HIV-1 transcription through multiple mechanisms. Here we show that HIV-1 gene expression can be induced by potent synthetic analogues of the lipid second messenger diacylglycerol (DAG) synthesized on a five-member ring platform that reduces the entropy of binding relative to that of the more flexible DAG template. By varying the alkyl side chains of these synthetic DAG lactones, it was possible to maximize their potency and ability to render latently infected T cells sensitive to killing by an anti-HIV-1 immunotoxin while minimizing the side effects of CD4 and CXCR4 downregulation and tumor necrosis factor alpha upregulation. The two lead compounds, LMC03 and LMC07, regulated a series of PKC-sensitive genes involved in T-cell activation and induced viral gene expression in peripheral blood mononuclear cells from HIV-1-infected individuals. These studies demonstrate the potential for the rational design of agents that, in conjunction with HAART and HIV-specific toxins, can be used to decrease or eliminate the pool of latently infected reservoirs by forcing viral expression.