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

• Published in: Bioorganic & medicinal chemistry letters 2001-07, Vol.11 (14), p.1897-1902
• Main Authors: TAMAMURA, Hirokazu, OMAGARI, Akane, NAKASHIMA, Hideki, OTAKA, Akira, FUJII, Nobutaka, HIRAMATSU, Kenichi, GOTOH, Kazuyo, KANAMOTO, Taisei, YOUNONG XU, KODAMA, Eiichi, MATSUOKA, Masao, HATTORI, Toshio, YAMAMOTO, Naoki
• Format: Article
• Language: English
• Subjects: Animals; Anti-HIV Agents - blood; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Anti-HIV Agents - toxicity; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cats; Cell Survival - drug effects; Circular Dichroism; Citrulline - chemistry; Drug Stability; HIV-1 - drug effects; Humans; Inhibitory Concentration 50; Medical sciences; Oligopeptides - chemistry; Oligopeptides - pharmacology; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Pharmacology. Drug treatments; Receptors, CXCR4 - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/s0960-894x(01)00323-7

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 ([Cit(6)]-T140 with the C-terminal amide) and TC14012 ([Cit(6), D-Cit(8)]-T140 with the C-terminal amide), which possess high selectivity indexes (SIs) and complete stability in feline serum.