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5-methylindole moiety of 30 is smaller than that of the
tricyclic Fmoc group. Consequently, this may result in
the loss of favorable p–p interactions with Phe229. Even
though 30 shows lower potency than 21 (1.8 vs 5.6 lM,
respectively), the 5-methylindolyl group would be the
best N-terminal moiety for replacing the base-labile
Fmoc group among the current series. The superim-
posed conformations of 30 and 31 reveal that the orien-
tation of the indole moiety of 31 is different from that of
30 or 21. Binding of 31 to the YopH catalytic site might
be hampered by its unfavorable steric interactions lead-
ing to loss of activity. Peptides 33 and 34 with thymine
and tetrazole moieties, respectively, demonstrated poor
inhibition of both YopH and PTP1B. Bis-amino tripep-
tides 35 and 36 were designed to explore the structural
transition from asymmetric monoamino acid analog 21
to symmetric bis-amino acid analog 36 via diamino-
propionic acid (Dap) containing 35. These were well tol-
erated and weakly influenced the inhibition against both
YopH and PTP1B.
In conclusion, modification of a promising series of pre-
viously described monoanionic pTyr mimetic-based
PTP inhibitors within a similar tripeptide platform 22–
24 resulted in significant inhibitory potencies but poor
selectivity against both YopH and PTP1B similar to the
previously reported 21. Introduction of the 5-methyl-
indolyl group at the N-terminus resulted in the potent
inhibitor 30, which indicated that the 5-methylindolyl
group is an effective replacement for the base-labile
Fmoc group. Molecular modeling studies examined
plausible interactions of the tripeptides with YopH at
the molecular level. Taken together, the current study
advances the understanding of structural features that
influence the PTP-inhibitory activity for this class of
compounds. It also offers new possibilities for improve-
ments in the selectivity index of tripeptides as potential
leads for PTP inhibitor design.
11. Leung, C.; Grzyb, J.; Lee, J.; Meyer, N.; Hum, G.; Jia,
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Pharm. Des. 1997, 3, 291.
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Biopolymers 2001, 60, 32.
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Res. Commun. 1994, 204, 129.
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Acknowledgments
19. Burke, T. R.; Ye, B.; Akamatsu, M.; Ford, H.; Yan, X. J.;
Kole, H. K.; Wolf, G.; Shoelson, S. E.; Roller, P. P.
J. Med. Chem. 1996, 39, 1021.
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L.; Zhang, Z.-Y.; Voigt, J. H. Tetrahedron 1998, 54, 9981.
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923.
L.W. and Z.-Y.Z. were supported by National Institute
of Health Grant 1U54 AI57158. We thank Dr. Shinya
Oishi for help in HPLC purifications.
References and notes
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