DRUG DISCOVERY BY MIRROR IMAGE LIGAND DISPLAY

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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.