H. Tamamura et al. / Bioorg. Med. Chem. Lett. 12 (2002) 923–928
927
partly assumed the b-sheet structure. This result is
compatible with that of CD spectroscopy. T(E)-140-OH
frayed in its N- and C-terminal tails.
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The difference in the solution structure from Arg6 to
Arg11 between T140 and T(E)-140-OH did not cause
significant reduction in anti-HIV activity or CXCR4-
inhibitory activity. According to our previous SAR
study, Arg2, Nal3, Tyr5 and Arg14 are indispensable
residues, which form the intrinsic pharmacophore of
anti-HIV activity and CXCR4-inhibitory activity.18
Taken together, the third-dimensional structure from
Arg6 to Arg11 of T140 might not be significantly
important for each activity. The region of Arg2-Nal3-
Cys(S-)4-Tyr5 and Cys(S-)13-Arg14, which are linked by
the disulfide bridge, is thought to be critical for the
activity, although the backbones of Arg2-Nal3 and
Arg14 were found to be flexible.
In conclusion, the pseudopeptide T(E)-140-OH, in
which an EADI was inserted into the (i+1)–(i+2) resi-
due of the bII0 turn, exhibited strong anti-HIV activity
and CXCR4-inhibitory activity comparable to those of
the parent peptide T140, while its solution structure is
different from that of T140, particularly in the turn
region, which is not critical for each activity. In this
case, partial nonpeptidylation was successful in terms of
activity, although an EADI did not serve as a promoter
of a bII0-turn structure. Our further study on non-
peptidylation of T140 will be followed to develop effi-
cient CXCR4 inhibitors based on T140. In addition, we
wish to investigate whether EADIs promote b- or bII-
hairpin formation in other compounds in solution.
5. Mitsuya, H.; Erickson, J. In Textbook of AIDS Medicine;
Merigan, T. C., Bartlett, J. G., Bolognesi, D., Eds.; Williams
& Wilkins: Baltimore, 1999; p 751.
Acknowledgements
6. Tamamura, H.; Kuroda, M.; Masuda, M.; Otaka, A.;
Funakoshi, S.; Nakashima, H.; Yamamoto, N.; Waki, M.;
Matsumoto, A.; Lancelin, J. M.; Kohda, D.; Tate, S.; Inagaki,
F.; Fujii, N. Biochim. Biophys. Acta 1993, 1163, 209.
7. Tamamura, H.; Arakaki, R.; Funakoshi, H.; Imai, M.;
Otaka, A.; Ibuka, T.; Nakashima, H.; Murakami, T.; Waki,
M.; Matsumoto, A.; Yamamoto, N.; Fujii, N. Bioorg. Med.
Chem. 1998, 6, 231.
8. Tamamura, H.; Xu, Y.; Hattori, T.; Zhang, X.; Arakaki,
R.; Kanbara, K.; Omagari, A.; Otaka, A.; Ibuka, T.; Yama-
moto, N.; Nakashima, H.; Fujii, N. Biochem. Biophys. Res.
Commun. 1998, 253, 877.
The authors wish to thank Drs. Hiromu Habashita,
Yoshihiko Odagaki and Nobuyuki Hamanaka from
Minase Research Institute, Ono Pharmaceutical Co.,
Ltd. for NMR analysis and technical assistance. This
work was supported in part by a Grant-in-Aid for Sci-
entific Research from the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan and the
Japan Health Science Foundation. Computation times
were provided by the Supercomputer Laboratory,
Institute for Chemical Research, Kyoto University.
9. (a) Tamamura, H.; Sugioka, M.; Odagaki, Y.; Omagari, A.;
Kan, Y.; Oishi, S.; Nakashima, H.; Yamamoto, N.; Peiper,
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Lett. 2001, 11, 359. (b) Tamamura, H.; Sugioka, M.; Odagaki,
Y.; Omagari, A.; Kan, Y.; Oishi, S.; Nakashima, H.; Yama-
moto, N.; Peiper, S. C.; Hamanaka, N.; Otaka, A.; Fujii, N.
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Tamamura, H.; Yamashita, M.; Muramatsu, H.; Ohno, H.;
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