DRUG DISCOVERY BY MIRROR IMAGE LIGAND DISPLAY

我是一名内科科学家，拥有核酸生物化学博士学位，在布里格姆妇女医院完成解剖病理学实习不到一年。在离开实验室三年后，我的当前目标是恢复研究，在布莱克洛博士在布里格姆妇女医院病理科的实验室学习蛋白质生物化学和结构领域的知识。这将给我必要的培训，以实现我在蛋白质药理学方面的翻译研究的长期目标。这些研究的总体目标是测试使用镜像噬菌体展示方法开发D-肽候选药物的可行性(Schumacher等人，1996；Forster，1996；图1)。本建议的具体目的是：1.确定选定的D-白介素8的L多肽配体的D-对映体与L-白介素8特异地结合，并具有可测量的亲和力。2.研究D-肽与白介素8靶标亲和力和特异性的分子间相互作用。3.将这一药物发现策略应用于其他潜在的治疗靶点，包括艾滋病毒包膜糖蛋白的gp41亚单位和乳腺癌特有的细胞表面糖蛋白MUC1。

I am a physician-scientist with a Ph.D. in nucleic acid biochemistry who is within a year of completing an anatomical pathology residency at the Brigham and Women's Hospital. My immediate goal is to resume research, after a three-year absence from the laboratory, to learn the fields of protein biochemistry and stucture in the laboratory of Dr. Blacklow at the Brigham and Women's Hospital, Department of Pathology. This will give me the training necessary to pursue my long term goal of translational research in protein pharmacology. The overall goal of these studies is to test the feasibility of developing D-peptide drug candidates using the method of mirror image phage display (Schumacher et al., 1996; Forster, 1996; Fig. 1). The specific aims of this proposal are: 1. To establish that the D-enantiomer of a selected L-peptide ligand of D-interleukin-8 binds specifically and with measurable affinity to L-interleukin-8. 2. To investigate the specific molecular interactions responsible for the measured affinity and specificity of the D-peptide for the interleukin-8 target. 3. To apply this strategy for drug discovery to other potential therapeutic targets, including the gp41 subunit of the HIV envelope glycoprotein and the breast-cancer specific, cell- surface glycoprotein MUC1.