ELONGATION FACTOR-3: A TARGET FOR ANTICRYPTOCOCCAL DRUGS

蛋白质合成因子EF-3显然是真菌所独有的，没有 存在于原核生物、植物或动物中的类似因子。 因此，我们认为， EF-3为抗隐球菌药物的开发提供了一个独特的靶点 可能还有广谱抗真菌药物， 治疗艾滋病患者的一系列其他机会性感染。 EF-3在其与核糖体的相互作用中起着复杂的生化作用， 氨酰tRNA，三核苷酸和其他延伸因子，使 EF-3和核糖体之间的界面是模型化的 抑制剂. 我们建议用分子遗传学和 具有以下特定目的的生化分析： 1.为了证明EF-3在结构和功能上是保守的， 真菌，因此是广谱抗真菌剂的合适靶标。 2.确定EF-3与核糖体相互作用的区域， 所涉及的残基及其相互作用的性质。 3.鉴定与EF-3相互作用的核糖体组分， 其绑定接口的性质。 我们的长期目标包括EF-3的结构-功能研究 蛋白质，并通过合作，三维分析的 结合位点。 这些研究应提供必要的信息， 设计隐球菌特异性和真菌特异性抗菌剂， 或者没有毒副作用。

The protein synthesis factor EF-3 is apparently unique to fungi, with no analogous factor present in prokaryotes, plants or animals. Therefore, EF-3 provides a unique target for the development of anticryptococcal agents and perhaps broad spectrum antifungal drugs which would be important in treating a range of other opportunistic infections in AIDS patients. EF-3 plays a complex biochemical role in its interaction with ribosomes, aminoacyl tRNA, trinucleotides and other elongation factors, making the interface between EF-3 and the ribosome a suitable target for a modeled inhibitor. We propose to define this interface with molecular genetic and biochemical analyses with the following specific aims: 1. To demonstrate that EF-3 is structurally and functionally conserved in fungi and thus a suitable target for a broad spectrum antifungal. 2. Identify the region of EF-3 which interacts with the ribosome, the residues involved and the nature of their interaction. 3. Identify the components of the ribosome which interact with EF-3 and the nature of their binding interface. Our long-range goals include structure-function studies of the EF-3 protein, and by way of collaboration, a 3-dimensional analysis of the binding sites. These studies should provide the information necessary to design cryptococcal-specific and fungal-specific antimicrobials with little or no toxic side effects.