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タイトル: Electrostatically constrained α-helical peptide inhibits replication of HIV-1 resistant to enfuvirtide.
著者: Nishikawa, Hiroki
Nakamura, Shota
Kodama, Eiichi
Ito, Saori
Kajiwara, Keiko
Izumi, Kazuki
Sakagami, Yasuko
Oishi, Shinya  kyouindb  KAKEN_id
Ohkubo, Tadayasu
Kobayashi, Yuji
Otaka, Akira
Fujii, Nobutaka  KAKEN_id
Matsuoka, Masao  KAKEN_id
著者名の別形: 大石, 真也
児玉, 栄一
キーワード: HIV
Fusion
Peptide
Inhibitor
α-Helix
発行日: Apr-2009
出版者: Elsevier
誌名: The international journal of biochemistry & cell biology
巻: 41
号: 4
開始ページ: 891
終了ページ: 899
抄録: Alpha-helical peptides, such as T-20 (enfuvirtide) and C34, derived from the gp41 carboxyl-terminal heptad repeat (C-HR) of HIV-1, inhibit membrane fusion of HIV-1 and the target cells. Although T-20 effectively suppresses the replication of multi-drug resistant HIV variants both in vitro and in vivo, prolonged therapy with T-20 induces emergence of T-20 resistant variants. In order to suppress the emergence of such resistant variants, we introduced charged and hydrophilic amino acids, glutamic acid (E) and lysine (K), at the solvent accessible site of C34. In particular, the modified peptide, SC34EK, demonstrates remarkably potent inhibition of membrane fusion by the resistant HIV-1 variants as well as wild-type viruses. The activity was specific to HIV-1 and little influenced by serum components. We found a strong correlation between the anti-HIV-1 activities of these peptides and the thermostabilities of the 6-helix bundles that are formed with these peptides. We also obtained the crystal structure of SC34EK in complex with a 36 amino acid sequence (N36) comprising the amino-terminal heptad repeat of HIV-1. The EK substitutions in the sequence of SC34EK were directed toward the solvent and generated an electrostatic potential, which may result in enhanced alpha-helicity of the peptide inhibitor. The 6-helix bundle complex of SC34EK with N36 appears to be structurally similar to that of C34 and N36. Our approach to enhancing alpha-helicity of the peptide inhibitor may enable future design of highly effective and specific HIV-1 inhibitors.
著作権等: © 2009 Elsevier B.V.
This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。
URI: http://hdl.handle.net/2433/137209
DOI(出版社版): 10.1016/j.biocel.2008.08.039
PubMed ID: 18834950
出現コレクション:学術雑誌掲載論文等

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