TY - JOUR
T1 - Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140
AU - Tamamura, Hirokazu
AU - Omagari, Akane
AU - Hiramatsu, Kenichi
AU - Gotoh, Kazuyo
AU - Kanamoto, Taisei
AU - Xu, Younong
AU - Kodama, Eiichi
AU - Matsuoka, Masao
AU - Hattori, Toshio
AU - Yamamoto, Naoki
AU - Nakashima, Hideki
AU - Otaka, Akira
AU - Fujii, Nobutaka
N1 - Funding Information:
The authors thank Dr. D. R. Littman, Skirball Institute for BioMolecular Medicine, New York University Medical Center, New York, USA, for providing U87.CD4.CCR5 and U87.CD4.CXCR4 cells, pNL4-3-Luc-E − R − and psp272-89.6. The authors are also grateful to Dr. C. Weiss, CBER, FDA, Bethesda, MD, USA, for providing pSMHXB2, and to Dr. A. Koito, Center for AIDS Research, Kumamoto University, Japan, for providing pSMSF162. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan and the Japan Health Science Foundation.
PY - 2001/7/23
Y1 - 2001/7/23
N2 - 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.
AB - 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.
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U2 - 10.1016/S0960-894X(01)00323-7
DO - 10.1016/S0960-894X(01)00323-7
M3 - Article
C2 - 11459656
AN - SCOPUS:0035939252
VL - 11
SP - 1897
EP - 1902
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 14
ER -