| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2001: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Teromerases, a family of reverse transcription enzymes, show potent activity in tumor and generative cells, and utilizes RNA as a mold (referred to teromerase RNA) on elongating the repeating DNA sequences, which feature the teromea structure, at the 3'-terminus of DNA. After elongating the several times of the repeating DNA sequences, the complement RNA is synthesized and works as a primer and duplication of DNA proceeds. As a result, the duplicated DNA is no shorter than the original DNA, and both the primer RNA and the teromerase RNA should have the same base sequences "UAACCCUAA". Therefore, mimetics of primer RNA (equivalent to teromerase RNA) could be an excellent candidate of novel medicines that regulates teromerase activities to ssuppress the endless growth of tumor cells, of which teromerase activity is high.
Now, we designed a peptide mimetic of the primer RNA (peptidic RNA) as an inhibitor of teromerases, and embarked on the synthetic study. At first, the acetaldehyde derivatives having uracil (U), adenine (A), or cytosine (C) residue at α-carbon were respectively treated with glycine in the presence of L-threonine aldolase to afford β-hydroxy-α-L-ammo acids carrying the RNA bases at γcarbon (The amino acids are abbreviated as γU-Thr, γA-Thr, γC-Thr). The amino acids were derived to benzyl esters, and followed by the reaction with Boc-Gly-Osu to give dipeptides, Boc-Gly-γUThr(Obn), Boc-Gly-γAThr(Obn), and Boc-Gly-γCThr(Obn). The conventional peptide synthesis using DCC/HOBt/NMM, deprotection of Boc with HC1, and cleavage of benzyl ester by alkaline hydrolysis or hydrogenation were repeated, and this synthetic procedure linking the dipeptides correctly gave two identified hexa-peptides having UAA or CCC codes on the residues. Final stage for the synthesis of the target peptidic RNA coding UAACCCUAA bases is in progress and will be accomplished in the near future.
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