Molecular design of anti-AIDS drugs targeting the viral and host zinc proteins

HIV RNA在感染后被逆转录并随后整合到宿主细胞的基因组中。这样形成的原病毒保持潜伏状态，直到某些刺激激活整合病毒基因的转录。多种病毒和宿主蛋白参与病毒基因的转录，被认为是治疗艾滋病的重要分子靶点。在本研究中，我们对整合酶、h - κ b、HIV- ep1、Sp1和HIV Tat感兴趣。它们都是锌蛋白或与锌密切相关的蛋白。我们研究了含一个吡啶和两个螯合侧链的锌结合人工分子的设计和合成，目的是抑制各种锌蛋白的功能。2003年，我们尝试在吡啶环上引入芳香取代基，并检测了羟肟酸和半胱胺作为螯合侧链。我们制备了含有苯基- 2-苯基、3-苯基、4-苯基、3,5双（三氟甲基）苯基、3,4-二甲氧基苯基、1-萘基、3-氯苯基取代基的吡啶。含1-萘基的锌螯合剂对Ras蛋白信号转导中重要的锌蛋白法尼基转移酶具有抑制作用，IC_<50> 1.9 μM。该化合物在浓度为0.5 μg/ml时诱导K-ras-NRK细胞形态改变，对K-ras-NRK细胞的生长抑制作用为IC_<50 bb0 0.32 μg/ml。2004年，研究了金三羧酸、没食子酸、香豆素衍生物等多酚类羧酸对NFκB DNA结合的抑制作用。Evans蓝对NFκB的DNA结合也有抑制作用。分子模型研究为这种抑制提供了一种解释。因此，我们成功地合成了抑制艾滋病相关锌蛋白功能的新化合物。

HIV RNA is reversetranscribed upon infection and subsequently integrated into the genome of the host cell. The provirus thus formed remains latent until certain stimuli activate the transcription of the integrated viral genes. Various viral and host proteins are involved in the transcription of viral genes and are regarded as significant, molecular targets for the treatment of AIDS.In the present study, we are interested in integrase, HFκB, HIV-EP1, Sp1 and HIV Tat. All of them are zinc proteins or that closely related to zinc.We have studied on the design and synthesis of zinc-binding artificial molecules containing a pyridine and two chelating side chains, aiming at the inhibition of the function of various zinc proteins. In 2003, we attempted the introduction of aromatic substituents onto the pyridine ring and examined hydroxamic acid in addition to cysteamine as the chelating side chains. We prepared pyridines bearing phenyl 2-tolyl, 3-tolyl, 4-tolyl, 3,5bis(trifluoromethyl)phenyl, 3,4-dimethoxyphenyl, 1-naphthyl,3-chlorophenyl substituents. A zinc chelator having 1-naphthyl group was found to be inhibitory against the farnesyltransferase, an important zinc protein in the signal transduction of Ras protein, with IC_<50> 1.9 μM. This compound induced morphological change in K-ras-NRK cells at.0.5 μg/ml and showed growth inhibition of K-ras-NRK cells with IC_<50> 0.32 μg/ml.In 2004, the inhibitory effect of polyphenol carboxylic acids, such as aurintricarboxylic acid, gallic acid, and coumarin derivatives on the DNA binding of NFκB were studied. Evans blue was also found to be inhibitory against the DNA binding of NFκB. Molecular modeling studies suggest an explanation for the inhibition.Thus, we are successful in the synthesis of novel compounds that inhibit function of zinc proteins related to AIDS.