CELLULAR INTERACTIONS OF BIOLOGICALLY ACTIVE AGENTS

识别与病毒感染、癌症、动脉粥样硬化、糖尿病、关节炎和神经退行性疾病有关的细胞成分将为抗击这些疾病创造新的机会。细胞膜的分子事件在这些健康问题中起着关键作用。在许多情况下，所涉及的细胞机械的身份尚不清楚。通过使用生物活性天然产物的结构修饰变体，研究的目标是(I)揭示与膜信号和运输有关的重要细胞相互作用，(Ii)更好地了解这些细胞成分的结构、功能和调节，以及(Iii)识别新的细胞实体，这些新细胞实体是控制一些疾病的有用靶点。(-)-伊利马喹酮是一种海绵代谢物，已被用于更好地了解囊泡运输。咪喹酮通过干扰S腺苷同型半胱氨酸酶抑制囊泡介导的分泌。激活的甲基循环中的一种酶。拟议的研究探索了伊利马喹酮与这一重要的抗病毒靶点的相互作用，以及确定调节囊泡介导的分泌的特定甲基化事件。类似地，将确定这些环孢菌素内酯的细胞相互作用，以帮助理解它们强大的抗炎作用。同样，洞察二十烷基前列腺素的生理作用，这是一项新发现。一类膜代谢物，将使用这些内源分子的官能化衍生物来实现。这些跨学科的研究将有助于确定负责调控膜运输和信号转导的各个方面的相互作用。随着对这些事件有了更好的描述，从根本上说，通过有选择地干扰贩运和信号传递功能来控制疾病的新方法应该变得可行。转运抑制剂可以提供一种降低胆固醇水平的新方法，抑制病毒感染的第一步，或调节β-淀粉样蛋白的分泌。在一个相关的问题上，对广泛的其他疾病的治疗可能受益于选择性的内吞作用抑制剂。例如，对药物治疗不敏感的患者可以从抑制药物受体内吞下调的化合物中受益。由于这些原因，进一步了解配体与膜化合物相互作用的细节将是非常有益的。

Identifying the cellular components involved in viral infection, cancer, atherosclerosis, diabetes, arthritis, and neurodegenerative disease will generate new opportunities to combat these afflictions. Molecular events of the cell membrane play pivotal roles in a variety of these health concerns. In many cases, the identify of cellular machinery involved is not known. Through the use of structurally modified variants of biologically active natural products, the research objective is to (i) reveal important cellular interactions involved in membrane signaling and trafficking, (ii) provide a better understanding of the structure, function, and regulation of these cellular components, and (iii) identify new cellular entities that are useful targets fro controlling a number of diseases. (-)-Ilimaquinone, a sponge metabolite, has been used to gain a better understanding of vesicular trafficking. Ilimaquinone inhibits vesicle- mediated secretion through its interference with S- adenosylhomocysteinase. An enzyme in the activated methyl cycle. The proposed studies explore the ilimaquinone's interact with this important antiviral target, as well as to determine the specific methylation events regulating vesicle-mediated secretion. Similarly, the cellular interactions of the cacospongionolids will be determined to help understand their potent anti-inflammatory action. Likewise, insight into the physiological role of the icoprostanes, a newly discovered. class of membrane metabolites, will be achieved using functionalized derivatives of these endogenous molecules. These interdisciplinary studies will help identify interactions responsible for regulating various aspects of membrane trafficking and signaling. With a better description of these events, fundamentally new approaches for controlling disease through the selective interference of trafficking and signaling functions should become feasible. Inhibitors of trafficking could provide a new means of lowering cholesterol levels, inhibiting the first steps in viral infection, or regulating the secretion of the beta- amyloid protein. In a related matter, treatments for a wide range of other illnesses potentially could benefit from selective inhibitors of endocytosis. For instance, patients that are desensitized to ascertain drug therapy could benefit from compounds that inhibit the endocytotic down- regulation of the drug's receptor. For these reasons, further knowledge of the details of ligand interactions with membrane compounds should be of substantial benefit.