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

HIV RNA在感染后逆转录，随后整合到宿主细胞的基因组中。这样形成的前病毒保持潜伏状态，直到某些刺激激活整合的病毒基因的转录。各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、HFκB、HIV-EP 1、Sp1和HIV达特进行了研究。本论文以抑制多种锌蛋白的功能为目标，设计合成了含一个吡啶和两个螯合侧链的锌结合人工分子。在2003年，我们尝试在吡啶环上引入芳族取代基，并研究了异羟肟酸以及半胱胺作为螯合侧链。我们合成了带有苯基、2-甲苯基、3-甲苯基、4-甲苯基、3，5-二（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类化合物。含1-萘基的锌螯合剂对Ras蛋白信号转导中的重要锌蛋白-法尼基转移酶有抑制作用，IC_（<50>1.9）μM。该化合物在0.5 μg/ml时可引起K-ras-NRK细胞的形态学改变，对K-ras-NRK细胞的生长有抑制作用，IC_（<50>0.32）μg/ml。2004年，研究了多酚羧酸类化合物如金精三羧酸、没食子酸和香豆素衍生物对NFκB DNA结合的抑制作用。Evans蓝对NFκB的DNA结合也有抑制作用。分子模拟研究对这种抑制作用给出了解释，因此，我们成功地合成了抑制艾滋病相关锌蛋白功能的新型化合物。

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.