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

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Gao Y, Voigt J, Zhao H, Pais GC, Zhang X, Wu L, Zhang ZY, Burke TR Jr

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

J Med Chem. 2001 Aug 30;44(18):2869-78.

PubMed ID

11520195 [ View in PubMed

]

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) (K(i) = 0.2 microM) and when Xxx = 3-carboxy-4-carboxymethyloxyphenylalanyl (K(i) = 3.6 microM). In the first instance, further work led from the F2Pmp-containing peptide to monomeric inhibitor, 6-(phosphonodifluoromethyl)-2-naphthoic acid (K(i) = 22 microM), and to the pseudo-dipeptide mimetic, N-[6-(phosphonodifluoromethyl)-2-naphthoyl]-glutamic acid (K(i) = 12 microM). 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 (K(i) = 900 microM). 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 degrees 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 K(i) = 31 +/- 7 microM, 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
4-Carbamoyl-4-{[6-(Difluoro-Phosphono-Methyl)-Naphthalene-2-Carbonyl]-Amino}-Butyric Acid	Tyrosine-protein phosphatase non-receptor type 1	Ki (nM)	12000	N/A	N/A	Details
6-(DIFLUORO-PHOSPHONO-METHYL)-NAPHTHALENE-2-CARBOXYLIC ACID	Tyrosine-protein phosphatase non-receptor type 1	Ki (nM)	22000	N/A	N/A	Details