Discovery of Cyclic Peptide Estrogens and Antiestrogens
Annual Summary rept. 22 Aug 2002-21 Apr 2003
PENNSYLVANIA STATE UNIV UNIVERSITY PARK
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Identification of proteins involved in the initiation of disease and the identification of small molecules that can modulate these proteins are of great importance towards the discovery of treatments for human chemotherapy. For example, compounds that potentiate estrogen receptor-mediated gene expression comprise a large class of currently employed chemotherapeutics. These compounds are employed to both treat breast cancer and provide hormone replacement therapy. Although initially beneficial, over time current clinically prescribed compounds can exhibit deleterious side-effects that include the development of drug resistance and an increased risk of breast cancer. We initially hypothesized that a recently described genetic system termed split-intein mediated circular ligation of peptides and proteins SICLOPPS PNAS, 1999, 96, 13638- 13643 could enable the identification of small cyclic peptides that exhibit estrogenic and antiestrogenic activity in recombinant yeast systems. However, preliminary data suggests that SICLOPPS does not function or express well in yeast. Current efforts are directed at using related systems to investigate oncogenic protein tyrosine kinases and to identify estrogenic proteins. These investigations may identify and potentiate critical protein interactions involved in the proliferation of breast cancer.
- Medicine and Medical Research