臺灣國際科展

Synthetic Analogs of Smoothened Intracellular Loop as Potent Inhibitors of Cancer Cells Growth

科展類別
臺灣國際科展
屆次
2008年
科別
化學科
得獎情形
第一名
學校名稱
Middletown Senior High School
指導老師
Bonnie Greaves Remsberg
作者
Jarrett Renn Remsberg

摘要或動機

Smoothened (SMO) is a critical component of Hedgehog (HH) pathway that is essential for stem cell renewal and is dysregulated in many cancer types. SMO is a seven transmembrane domain protein with three intracellular loops. Primary structures of SMO intracellular loops are unique and very much conserved among the species, which is indicative of significant and unique roles in intermolecular or intramolecular interactions. The hypothesis was that synthetic analogs of SMO intracellular loops may function as HH pathway inhibitors. Derivatives of second intracellular loop were synthesized utilizing automated solid phase peptide synthesis based on Fmoc chemistry. Peptides were purified by HPLC and there anti-proliferative activity tested on melanoma cells by MTT assay. Targeted libraries of second loop derivatives of varying length helped to identify compounds that inhibited the growth of melanoma cells in vitro with IC50 in nanomolar range. The most potent of antagonists obtained is the palmitoyl derivative of the Nterminal half of the loop, and is 12 residues long. Lipidation proved to be critical for the activity. Remarkably, retro-inverso versions of the peptide, in which all amino acids are in D-configuration, are even more potent and have IC50 in subnanomolar range. Circular dichroism studies proved that the peptides are folded both in aqueous solutions and in the presence of lipids mimicking the membrane environment. They also suggested that retroinverso analogs have a different fold, which may contribute to higher activity. The new compounds are promising drug candidates and present convenient tools for solving the\r
mechanisms of hedgehog signaling.


「為配合國家發展委員會「推動ODF-CNS15251為政府為文件標準格式實施計畫」,以及 提供使用者有文書軟體選擇的權利,本館檔案下載部分文件將公布ODF開放文件格式, 免費開源軟體可至LibreOffice 下載安裝使用,或依貴慣用的軟體開啟文件。」

檔案名稱 檔案大小 格式
Synthetic Analogs of Smoothened Intracellular Loop as Potent Inhibitors of Cancer Cells Growth 61 KB Adobe Reader(Pdf)檔案