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（Brigham and Women's Hospital）完成解剖病理学实习不到一年。在离开实验室三年之后，我的近期目标是恢复研究，在布莱根妇女医院病理科的Blacklow博士的实验室学习蛋白质生物化学和结构领域。这将为我追求蛋白质药理学的长期转化研究目标提供必要的培训。这些研究的总体目标是测试利用镜像噬菌体展示的方法开发d肽候选药物的可行性（Schumacher et al., 1996; Forster, 1996；图1）。本建议的具体目的是：1。确定选定的l -肽配体的d -对映体与l -白细胞介素-8特异性结合，并具有可测量的亲和力。2. 研究导致d肽对白细胞介素-8靶标的亲和力和特异性的特定分子相互作用。3. 将这一策略应用于其他潜在的治疗靶点，包括HIV包膜糖蛋白的gp41亚基和乳腺癌特异性的细胞表面糖蛋白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.