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

Research output: Contribution to journalArticlepeer-review

110 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1897-1902
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume11
Issue number14
DOIs
Publication statusPublished - 2001 Jul 23
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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