Utilization of a peptide lead for the discovery of a novel PTP1B-binding motif

Y. Gao, J. Voigt, H. Zhao, G. C G Pais, X. Zhang, L. Wu, Zhong-Yin Zhang, T. R. Burke

Research output: Contribution to journalArticle

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Abstract

Examination of the PTP1B inhibitory potency of an extensive series of phosphotyrosyl (pTyr) mimetics (Xxx) expressed in the EGFr-derived hexapeptide platform Ac-Asp-Ala-Asp-Xxx-Leu-amide previously led to the finding of high inhibitory potency when Xxx = 4-(phosphonodifluoromethyl)phenylalanyl (F2Pmp) (Ki = 0.2 μM) and when Xxx = 3-carboxy-4-carboxy-methyloxyphenylalanyl (Ki = 3.6 μM). In the first instance, further work led from the F2Pmp-containing peptide to monomeric inhibitor, 6-(phosphonodifluoromethyl)-2-naphthoic acid (Ki = 22 μM), and to the pseudo-dipeptide mimetic, N-[6-(phosphonodifluoromethyl)-2-naphthoyl]-glutamic acid (Ki = 12 μM). In the current study, a similar approach was applied to the 3-carboxy-4-carboxymethyloxyphenylalanyl-containing peptide, which led to the preparation of monomeric 5-carboxy-6-carboxymethyloxy-2-naphthoic acid (Ki = 900 μM). However, contrary to expectations based on the aforementioned F2Pmp work, incorporation of this putative pTyr mimetic into the pseudo-dipeptide, N-[5-carboxy-6-carboxymethyloxy-2-naphthoyl]-glutamic acid, resulted in a substantial loss of binding affinity. A reevaluation of binding orientation for 5-carboxy-6-carboxymethyloxy-2-naphthoic acid was therefore undertaken, which indicated a 180° reversal of the binding orientation within the PTP1B catalytic site. In the new orientation, the naphthyl 2-carboxyl group, and not the o-carboxy carboxymethyloxy groups, mimics a phosphoryl group. Indeed, when 5-carboxy-2-naphthoic acid itself was examined at neutral pH for inhibitory potency, it was found to have Ki = 31 ± 7 μM, which is lower than parent 5-carboxy-6-carboxymethyloxy-2-naphthoic acid. In this fashion, 5-carboxy-2-naphthoic acid (or more appropriately, 6-carboxy-1-naphthoic acid) has been identified as a novel PTP1B binding motif.

Original languageEnglish (US)
Pages (from-to)2869-2878
Number of pages10
JournalJournal of Medicinal Chemistry
Volume44
Issue number18
DOIs
StatePublished - Aug 30 2001
Externally publishedYes

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Peptides
Dipeptides
Glutamic Acid
Amides
2-naphthoic acid
Catalytic Domain

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Gao, Y., Voigt, J., Zhao, H., Pais, G. C. G., Zhang, X., Wu, L., ... Burke, T. R. (2001). Utilization of a peptide lead for the discovery of a novel PTP1B-binding motif. Journal of Medicinal Chemistry, 44(18), 2869-2878. https://doi.org/10.1021/jm010020r

Utilization of a peptide lead for the discovery of a novel PTP1B-binding motif. / Gao, Y.; Voigt, J.; Zhao, H.; Pais, G. C G; Zhang, X.; Wu, L.; Zhang, Zhong-Yin; Burke, T. R.

In: Journal of Medicinal Chemistry, Vol. 44, No. 18, 30.08.2001, p. 2869-2878.

Research output: Contribution to journalArticle

Gao, Y, Voigt, J, Zhao, H, Pais, GCG, Zhang, X, Wu, L, Zhang, Z-Y & Burke, TR 2001, 'Utilization of a peptide lead for the discovery of a novel PTP1B-binding motif', Journal of Medicinal Chemistry, vol. 44, no. 18, pp. 2869-2878. https://doi.org/10.1021/jm010020r
Gao, Y. ; Voigt, J. ; Zhao, H. ; Pais, G. C G ; Zhang, X. ; Wu, L. ; Zhang, Zhong-Yin ; Burke, T. R. / Utilization of a peptide lead for the discovery of a novel PTP1B-binding motif. In: Journal of Medicinal Chemistry. 2001 ; Vol. 44, No. 18. pp. 2869-2878.
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AU - Wu, L.

AU - Zhang, Zhong-Yin

AU - Burke, T. R.

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N2 - Examination of the PTP1B inhibitory potency of an extensive series of phosphotyrosyl (pTyr) mimetics (Xxx) expressed in the EGFr-derived hexapeptide platform Ac-Asp-Ala-Asp-Xxx-Leu-amide previously led to the finding of high inhibitory potency when Xxx = 4-(phosphonodifluoromethyl)phenylalanyl (F2Pmp) (Ki = 0.2 μM) and when Xxx = 3-carboxy-4-carboxy-methyloxyphenylalanyl (Ki = 3.6 μM). In the first instance, further work led from the F2Pmp-containing peptide to monomeric inhibitor, 6-(phosphonodifluoromethyl)-2-naphthoic acid (Ki = 22 μM), and to the pseudo-dipeptide mimetic, N-[6-(phosphonodifluoromethyl)-2-naphthoyl]-glutamic acid (Ki = 12 μM). In the current study, a similar approach was applied to the 3-carboxy-4-carboxymethyloxyphenylalanyl-containing peptide, which led to the preparation of monomeric 5-carboxy-6-carboxymethyloxy-2-naphthoic acid (Ki = 900 μM). However, contrary to expectations based on the aforementioned F2Pmp work, incorporation of this putative pTyr mimetic into the pseudo-dipeptide, N-[5-carboxy-6-carboxymethyloxy-2-naphthoyl]-glutamic acid, resulted in a substantial loss of binding affinity. A reevaluation of binding orientation for 5-carboxy-6-carboxymethyloxy-2-naphthoic acid was therefore undertaken, which indicated a 180° reversal of the binding orientation within the PTP1B catalytic site. In the new orientation, the naphthyl 2-carboxyl group, and not the o-carboxy carboxymethyloxy groups, mimics a phosphoryl group. Indeed, when 5-carboxy-2-naphthoic acid itself was examined at neutral pH for inhibitory potency, it was found to have Ki = 31 ± 7 μM, which is lower than parent 5-carboxy-6-carboxymethyloxy-2-naphthoic acid. In this fashion, 5-carboxy-2-naphthoic acid (or more appropriately, 6-carboxy-1-naphthoic acid) has been identified as a novel PTP1B binding motif.

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