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ABSTRACT: A novel strategy that targets protein for degradation has recently been developed by exploiting a protein-targeting chimeric molecule ('Protac'). Typically, the chimeric Protac is composed of a small-molecule ligand ('bait') on one end and a synthetic octapeptide on the other. This octapeptide is recognized by E3 ubiquitin ligase pVHL (von Hippel Lindau tumor suppressor protein), thereby recruiting a small molecule-bound protein ('prey') to pVHL for ubiquitination and degradation. Since selective degradation of a cellular protein generates a "loss of function" mutation, this protein knock-out strategy may be useful to study the function of a given protein or to evaluate whether a cellular protein is a potential target for drug intervention, in a manner reminiscent of gene knock-out or siRNA approaches. Herein, we show that a synthetic pentapeptide is sufficient to interact with pVHL E3 ligase, and that the pentapeptide-based Protac efficiently induces ubiquitination and degradation of target protein. Our results also demonstrate that the pentapeptide-based Protac can enter cells efficiently to exerts its biological activity effectively. These results suggest that the synthetic pentapeptide can be used either directly in the preparation of cell-permeable Protacs or as a template to develop peptidomimetic or non-peptide Protacs.
Combinatorial Chemistry & High Throughput Screening 12/2004; 7(7):689-97. · 1.78 Impact Factor
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ABSTRACT: One approach for studying cocaine addiction has been to permit escalating patterns of self-administration (SA) by rats by prolonging daily drug availability. Rats provided long access (LgA) to high cocaine doses, but not rats provided shorter cocaine access (ShA), progressively escalate their cocaine intake and display characteristics of human addiction. The purpose of the present study was to investigate the effects of 14 days of ShA or LgA, high-dose cocaine SA on plasma corticosterone (CORT), prolactin (PRL), and related mRNAs. Acutely, cocaine SA increased plasma CORT and reduced plasma PRL levels. SA training produced circadian increases in CORT that appeared to occur in anticipation of cocaine availability. With repeated LgA, high-dose SA, the daily CORT area under the curve (AUC) progressively decreased, apparently due to tolerance to cocaine’s effects on CORT and a reduction in basal CORT levels. In contrast, the daily CORT AUC in ShA rats increased across testing despite constant rates of SA. When measured 12 days after SA testing, pro-opioimelanocortin and glucocorticoid receptor mRNA levels in the anterior pituitary were lower in LgA rats than in ShA rats. The effects of SA on PRL remained constant across SA testing in LgA rats, but increased in duration in ShA rats. Anterior pituitary dopamine D2 receptor mRNA levels were lower in LgA rats than in ShA rats. These findings indicate that the transition to escalating patterns of SA may be associated with altered levels of hormones and gene expression within neuroendocrine systems. Such changes may underlie the onset of human addictive disease.
Psychoneuroendocrinology.
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ABSTRACT: In recent work, various design techniques were applied to investigate the feasibility of controlling the bandwidth and bandshape profiles of tungsten/boron-carbon (W/B4C) and tungsten/silicon (W/Si) multilayers for optimizing their performance in synchrotron radiation based angiographical imaging systems at 33 keV. Varied parameters included alternative spacing geometries, material thickness ratios, and numbers of layer pairs. Planar optics with nominal design reflectivities of 30–94% and bandwidths ranging from 0.6–10% were designed at the Stanford Synchrotron Radiation Laboratory, fabricated by the Ovonic Synthetic Materials Company, and characterized on Beam Line 4-3 at the Stanford Synchrotron Radiation Laboratory. In this paper we report selected results of these tests and review the possible use of the multilayers for determining optimal signal to noise vs artifact signal ratios in practical dual-energy digital subtraction angiography systems.
Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment.
