84(P77) gp120-CD4結合を阻害するペプチド抗生物質chloropeptinの構造(ポスター発表の部)

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Chloropeptin, a novel peptide antibiotic isolated from a culture broth of S treptomyces sp. WK-3419, is a potent inhibitor of the binding between gp120 envelope glycoprotein of HIV-1 and the CD4 receptor of HIV-1 on the surface of human T cells (IC_<50> 32nM by the ELIS A method). Chloropeptin also inhibits the cytopathic effect assayed in HIV-1-infected Molt-4 cells (IC_<50> 1.6μM) and the syncitium formation in Molt-4 as well as HIV-1-infected Molt-4 cells (IC_<50> 0.7μM). We now report the absolute configuration of chloropeptin, elucidated via a combination of NMR, degradative and molecular modeling techniques. The molecular formula was determined by HR-FAB-MS to be C_<61>H_<45>N_7O_<15>Cl_6. The ^1H- and ^<13>C-NMR spectra indicated the presence of six aromatic amino acids and an oxoaromatic acid. The complete connectivity of chloropeptin was subsequently established utilizing COSY, HMQC and HMBC spectroscopy. Acid hydrolysis furnished (D)-4-hydroxyphenylglycine and (D)-3,5-dichloro-4-hydroxyphenylglycine; their absolute configurations were determined by optical rotation and chiral TLC. The stereochemistry at C_α of residues, tyrosine, 3,5-dihydroxyphenylglycine and tryptophan, were determined using a combination of high-temperature molecular dynamics (MD) calculations, NOE data, and J values. Among a lot of conformers obtained from the MD calculations, one satisfying all of distance and dihedral constraints could be found in case that the absolute stereochemistry at C_α of residue, tyrosine, 3,5-dihydroxyphenylglycine and tryptophan, was assigned as L, D, and D configuration, respectively.
天然有機化合物討論会の論文
1996-09-02

84(P77) gp120-CD4結合を阻害するペプチド抗生物質chloropeptinの構造(ポスター発表の部)

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