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Synthesis of Peptide Mimetics of RNA that Regulate the Activity of Teromerase

调节端粒酶活性的 RNA 肽模拟物的合成

基本信息

批准号：
13672209
负责人：
KAJIMOTO Tetsuya
金额：
$ 2.3万
依托单位：
Tokyo University of Agriculture and Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672209/
关键词：
teromerase primer RNA peptidic RNA L-threonine aldolase β-hydroxy-α-L-amino acid uracil adenine cytosine 逆転写酵素 RNA ペブチド性RNA テロメラーゼ阻害剤アデニン(A)ウラシル(U)DCC HOBt NMM法

项目摘要

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.

端粒酶是一类逆转录酶家族，在肿瘤和生殖细胞中显示出很强的活性，并利用RNA作为模板(称为畸形酶RNA)来延长DNA 3‘末端的重复DNA序列，该序列具有Teromea结构。在将重复的DNA序列延长几倍后，互补RNA被合成并作为引物进行DNA复制。因此，复制的DNA不会比原始DNA短，而且引物RNA和畸变酶RNA都应该具有相同的碱基序列UAACCCUAA。因此，模拟引物RNA(相当于畸变酶RNA)可能是一种很好的候选新药，通过调节畸变酶活性来抑制肿瘤细胞的无限生长，其中的畸变酶活性很高。现在，我们设计了一种模拟引物RNA的多肽(肽RNA)作为畸变酶的抑制物，并开始了合成研究。首先，在L-苏氨酸醛缩酶的催化下，将α碳上含有尿嘧啶(U)、腺嘌呤(A)或胞嘧啶(C)残基的乙醛衍生物分别与甘氨酸反应，得到β-羟基-α-L-氨基酸(简称γ-U-Thr、γA-Thr、γC-Thr)。将这些氨基酸衍生为苯甲酸酯，然后与Boc-Gly-Osu反应，得到Boc-Gly-γUTHR(OBN)、Boc-Gly-γTHR(OBN)和Boc-Gly-γCTHR(OBN)。重复使用DCC/HOBt/NMM合成多肽，用HCl去保护Boc，用碱性水解或氢化裂解苄酯，正确地将二肽连接在一起，得到了两个残基上具有UAA或CCC编码的六肽。合成编码UAACCCUAA碱基的目标多肽RNA的最后阶段正在进行中，将在不久的将来完成。