Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140

Hirokazu Tamamura, Akane Omagari, Kenichi Hiramatsu, Kazuyo Gotoh, Taisei Kanamoto, Younong Xu, Eiichi Kodama, Masao Matsuoka, Toshio Hattori, Naoki Yamamoto, Hideki Nakashima, Akira Otaka, Nobutaka Fujii

研究成果: Article査読

110 被引用数 (Scopus)

抄録

We previously reported a truncated polyphemusin peptide analogue, T140, which efficiently inhibits infection of target cells by T-cell line-tropic strains of HIV-1 (X4-HIV-1) through its specific binding to a chemokine receptor, CXCR4. We have found that T140 is not stable in feline serum due to the cleavage of the C-terminal Arg,14 indispensable for anti-HIV activity. On the other hand, a C-terminally amidated analogue of T140, TZ14004, has been found to be completely stable in incubation in the serum for 2 days. The C-terminal amide is thought to be needed for stability in serum. However, TZ14004 does not have fairly strong anti-HIV activity, but has relatively strong cytotoxicity, probably due to an increase by + 1 charge from total + 7 charges of T140. In our previous study, the number of total + 6 charges seemed to be a suitable balance between activity and cytotoxicity. In this study, we have conducted a double-L-citrulline (Cit)-scanning study on TZ14004 based on the C-terminally amidated form in due consideration of the total net charges in the whole molecule to find novel effective CXCR4 inhibitors, TN14003 ([Cit6]-T140 with the C-terminal amide) and TC14012 ([Cit6, D-Cit8]-T140 with the C-terminal amide), which possess high selectivity indexes (SIs) and complete stability in feline serum.

本文言語English
ページ(範囲)1897-1902
ページ数6
ジャーナルBioorganic and Medicinal Chemistry Letters
11
14
DOI
出版ステータスPublished - 2001 7 23
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 分子医療
  • 分子生物学
  • 薬科学
  • 創薬
  • 臨床生化学
  • 有機化学

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