CELLULAR INTERACTIONS OF BIOLOGICALLY ACTIVE AGENTS

识别病毒感染、癌症、动脉粥样硬化、糖尿病、关节炎和神经退行性疾病中涉及的细胞成分将为对抗这些疾病提供新的机会。细胞膜的分子事件在这些健康问题中发挥着关键作用。在许多情况下，涉及的细胞机器的识别是未知的。通过使用生物活性天然产物的结构修饰变体，研究目标是（i）揭示参与膜信号传导和运输的重要细胞相互作用，（ii）提供对这些细胞组分的结构，功能和调节的更好理解，以及（iii）确定新的细胞实体，这些实体是控制许多疾病的有用靶点。（-）-Iimaquinone是一种海绵代谢物，已被用于更好地了解囊泡运输。Iimaquinone通过干扰S-腺苷高半胱氨酸酶抑制囊泡介导的分泌.一种处于活化甲基循环中的酶。拟议的研究探索了与这个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。同样，将确定cacospongionolids的细胞相互作用，以帮助了解其有效的抗炎作用。同样，深入了解新发现的依考前列烷的生理作用。一类膜代谢物，将使用这些内源性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节膜运输和信号传导的各个方面的相互作用。随着对这些事件的更好描述，通过选择性干扰贩运和信号功能来控制疾病的根本性新方法应该变得可行。运输抑制剂可以提供一种降低胆固醇水平、抑制病毒感染的第一步或调节β-淀粉样蛋白分泌的新方法。与此相关的是，选择性内吞作用抑制剂可能会对多种其他疾病的治疗产生潜在的益处。例如，为了确定药物治疗而脱敏的患者可以从抑制药物受体的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应该是有很大好处的。

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.