2006
DOI: 10.1021/jm060036n
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Nanomolar Inhibitors of the Peptidyl Prolyl Cis/Trans Isomerase Pin1 from Combinatorial Peptide Libraries

Abstract: The peptidyl prolyl cis/trans isomerase Pin1 has been implicated in the development of cancer, Alzheimer's disease and asthma, but highly specific and potent Pin1 inhibitors remain to be identified. Here, by screening a combinatorial peptide library, we identified a series of nanomolar peptidic inhibitors. Nonproteinogenic amino acids, incorporated into 5-mer to 8-mer oligopeptides containing a d-phosphothreonine as a central template, yielded selective inhibitors that blocked cell cycle progression in HeLa ce… Show more

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Cited by 85 publications
(96 citation statements)
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“…To rule out a nonspecific effect of juglone, we used a more specific Pin1 inhibitor consisting of a competitive peptide containing a Pin1-binding sequence able to inhibit Pin1 both in vitro and in intact cells. 31 This PPIn also abrogated TNF-␣-induced priming of ROS production in response to fMLF ( Figure 2C-D), whereas its effect on fMLF stimulation alone was not significant. Importantly, neither juglone nor PPIn inhibited neutrophil ROS production triggered by PMA, a PKC direct activator ( Figure 2E-F), suggesting that these agents do not inhibit NADPH oxidase activity or the PKC-dependent activation pathway, and that they do not scavenge ROS.…”
Section: Pin1 Inhibitors Inhibit Tnf-␣-induced Priming Of Ros Productmentioning
confidence: 86%
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“…To rule out a nonspecific effect of juglone, we used a more specific Pin1 inhibitor consisting of a competitive peptide containing a Pin1-binding sequence able to inhibit Pin1 both in vitro and in intact cells. 31 This PPIn also abrogated TNF-␣-induced priming of ROS production in response to fMLF ( Figure 2C-D), whereas its effect on fMLF stimulation alone was not significant. Importantly, neither juglone nor PPIn inhibited neutrophil ROS production triggered by PMA, a PKC direct activator ( Figure 2E-F), suggesting that these agents do not inhibit NADPH oxidase activity or the PKC-dependent activation pathway, and that they do not scavenge ROS.…”
Section: Pin1 Inhibitors Inhibit Tnf-␣-induced Priming Of Ros Productmentioning
confidence: 86%
“…To raise antibodies against phosphoSer315, phospho-Ser320, and phospho-Ser328, rabbits were injected with the ovalbumin-crosslinked phosphopeptide sequences of these serines by PolyPeptide Laboratories. The Pin1-peptide inhibitor sequence (Ac-Phe-D-Thr(PO3H2)-Pip-Nal-Gln-NH2) 31 was synthesized by PolyPeptide Laboratories.…”
Section: Reagents and Antibodiesmentioning
confidence: 99%
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“…More specific Pin1 inhibitors with less side effects are required. Promising candidates are the substituted aryl 1-indanyl ketones (53) and a series of specific D-phospho-Thr-containing peptides (54,55). Such inhibitors might not only be useful in studying the functional relevance of Pin1 in vivo; they could also provide the therapeutic basis to treat pathological conditions in which Pin1 is aberrantly upregulated, such as cancer (8).…”
Section: Discussionmentioning
confidence: 99%
“…A few years later, a series of potent phosphorylated pentameric to octameric phosphorylated peptidic inhibitors of Pin1 activity was selected from a combinatorial library (Wildemann et al, 2006a). These inhibitors contained non-proteogenic amino acids and blocked cell cycle progression in HeLa cells in a dose-dependent manner.…”
Section: Peptidic Inhibitors and Substrate Analogsmentioning
confidence: 99%