6 プロテインキナーゼCのホルボールエステル結合部位を含むサロゲートペプチドの合成と化学的特性(口頭発表の部)

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Protein kinase C (PKC) is a key enzyme family involved in cellular signal transduction and tumor promotion. It consists of a catalytic domain for protein phosphorylation and a regulatory domain which binds the endogenous messenger diacyl glycerol or exogenous agents such as the phorbol ester-type tumor promoters. The phorbol ester-binding site in PKC is a cysteine-rich domain (CRD) at the N-terminal regulatory region. The CRD consisting of ca. 50 amino acids has six conserved cysteines and two histidines in the pattern HX_<12>CX_2CX_<13>CX_2CX_4HX_2CX_7C where X is a variable amino acid residue. With the discovery of at least eleven PKC isozymes, increasing importance is placed on isozyme specific analysis of function. Isozyme-selective activators or inhibitors represent powerful tools to analyze the role of PKC and become new medicinal leads for diseases related to PKC activation like the vascular complications by hyperglycemia. However, the rational development of such compounds has been hampered by limited information on the structure of the phorbol ester-PKC-phosphatidylserine aggregate. Since pure PKC isozymes are not easily obtainable from natural sources, the CRD's of PKC consisting of ca. 50 amino acids (γ-CRD1, γ-CRD2, η-CRD1, andη-CRD2) have been prepared by solid phase synthesis to establish the models of PKCγ and PKCη for development of new medicinal leads. These peptides were efficiently folded upon zinc treatment to produce PKC regulatory domain surrogates that bind [^3H]phorbol 12,13-dibutyrate (PDBu) with high affinity comparable to native PKC itself, suggesting that these peptides serve as effective models for native PKC. Tumor promoter analogues are most promising as lead compounds for isozyme selective activation or inhibition of PKC since they specifically recognize PKC. Using the PKC surrogate peptides, we have identified new ligands (4a, 4b) with high CRD selectivity based on our recently reported strategy for the design of conformationally restricted indolactam derivatives. Furthermore, we have found that cadmium ion would become an effective tool for controlling isozyme selective regulation of PKC. As exemplified in the PKC surrogate peptides, recent solid phase peptide synthesis as well as DNA recombination technique has brought a new drug design strategy.
天然有機化合物討論会の論文
1997-07-20

6 プロテインキナーゼCのホルボールエステル結合部位を含むサロゲートペプチドの合成と化学的特性(口頭発表の部)

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