Template Based Design of Anti-Metastatic Drugs from the Active Conformation of Laminin Peptide II
Annual rept. 1 Jan-31 Dec 2000
MONTANA STATE UNIV BOZEMAN
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Major advances were made towards elucidating the structure of the ligand-binding domain of the 67 kDa LBP. Phage display studies indicated that three sequence domains in the C-terminal domain of the LBP likely interact with peptide 11. Both GBl fusion domains and other cohesive domains of LBP, identified by limited proteolysis studies, have been expressed in recombinant bacterial systems. Well-dispersed NMR spectra have been generated for several of these, indicating that they will be useful for structure determination of the LBP ligand-binding domain. We now have a successful synthetic path for the candidate l6 YIGSR mimetic, which was designed by an early run of the INVENTON program. On receipt of sufficient material, this will shortly be investigated for its bioactivity. Structurally related compounds will be used in structureactivity studies to optimize the bioactivity of the mimetic. To facilitate the preclinical studies, metastatic variants of the MDA-MB-23l and MDA-MB-435 human breast cancer cell lines have been generated. Since we have found that LBP shedding is estrogen responsive, we have also derived more invasive variants of the T47D ERve breast cancer cell line. The LBP protein was shown to have a sulfhydryl oxidase activity, and facilitated peptide 11 dimerization.
- Medicine and Medical Research