1,721,209 research outputs found
Skp2 Inhibitors: Novel Anticancer Strategies
No full textSkp2 is frequently overexpressed in many human cancers and plays a key role in tumorigenesis. As a component of the SCFSkp2 ubiquitin E3 ligase complex, Skp2 is responsible for recruiting substrate proteins for their ubiquitination and subsequent degradation by the 26S proteasome. Thus, Skp2 promotes the cell cycle by down-regulating cell cycle proteins such as the tumor suppressor p27. Alternatively, Skp2 suppresses p53-dependent apoptosis by outcompeting p53 for binding to p300, thereby perturbing p300-mediated p53 acetylation and stabilization. Taken together, inhibition of Skp2 functions (either proteolytic function or non-proteolytic function) is emerging as a promising and novel anti-cancer strategy. In the present review, we highlight the development of Skp2 inhibitors with different mechanisms of action.1162Nsciescopu
Facile Method To Sequence Cyclic Peptides/Peptoids via One-Pot Ring-Opening/Cleavage Reaction
No full textA facile method for sequence determination of cyclic peptides/peptoids is described. Macrocyclic peptides/peptoids of 310 residues were efficiently synthesized through thioether formation. One-pot reaction of thioether-embedded cyclic peptides/peptoids involving cyanogen bromide-mediated ring-opening and cleavage provides linearized molecules, which can be efficiently sequenced by tandem mass spectrometry.X111310sciescopu
Synthesis and screening of small-molecule alpha-helix mimetic libraries targeting protein-protein interactions
No full textalpha-Helices are the most common protein secondary structure and play a key role in mediating many protein-protein interactions (PPIs) by serving as recognition motifs. Given that aberrant alpha-helix-mediated PPIs are linked to various disease states, targeting such interactions with small-molecules represents an attractive strategy to develop therapeutic candidates for the related diseases. Over the last decade, significant efforts have been directed toward developing alpha-helix mimetic small-molecules that can modulate alpha-helix-mediated PPIs. In this review, we will highlight recent advances in the development of non-peptidic, small-molecule alpha-helix mimetics with a focus on library synthesis and screening methods to efficiently discover small-molecule alpha-helix mimetics.X112420sciescopu
Solid-phase synthesis of tetrasubstituted pyrrolo[2,3-d]pyrimidines
No full textA facile solid phase synthesis of 2,4,6,7-tetrasubstituted pyrrolo[2,3-d]pyrimidines is described. The synthesis involves a highly efficient five-step route starting from resin-bound dimeric peptoids. To demonstrate the versatility of our method, a representative library of 108 tetrasubstituted pyrrolo[2,3-d] pyrimidines of high quality was synthesized.open111111sciescopu
GAMMA multidimensional multicomponent mixture analysis to predict air ingress phenomena in an HTGR
No full textWe developed a multidimensional GAs Multicomponent Mixture Analysis (GAMMA) code in order to investigate chemical reaction behaviors related to an air ingress accident and the thermofluid transients in high-temperature gas-cooled reactors. The implicit continuous Eulerian technique is adopted for the reduction of a 10N x 10N matrix into an N x N pressure difference matrix and fast transient computation. In the validation with a high-temperature engineering test reactor (HTTR)-simulated air ingress experiment, the onset times of natural convection are accurately predicted within a 10% deviation. Small internal leaks in the HTTR-simulated test facility have been found to significantly affect the consequence of air ingress. In all the simulated cases for a SANA-1 afterheat removal test, the predictions of GAMMA are in a high level of agreement with the measured temperature profiles and are comparable to the results of other codes (TINTS, THERMIX/DIREKT, and TRIO-EF)
Design and Facile Solid-Phase Synthesis of Conformationally Constrained Bicyclic Peptoids
No full textTriazine-bridged bicyclic peptoids as conformationally constrained peptidomimetics are described. Bicyclic peptoids composed of 6-12 peptoid residues (m, n = 3-6) were synthesized in excellent yields using a highly efficient solid-phase synthetic route.X112423sciescopu
Identification of a peptoid inhibitor of the proteasome 19S regulatory particle
No full textThe first chemical inhibitor of the 19S regulatory particle (RP) of the proteasome is described. The molecule was identified by screening a library of nucleoside-capped peptoids for binding to the yeast 26S proteasome in a crude extract. The hit was resynthesized and shown to block 19S RP-mediated protein unfolding in vitro and proteasome-mediated turnover of p27 in HeLa cells.X117877sciescopu
A simple strategy for the construction of combinatorial cyclic peptoid libraries
No full textHere we describe a simple method that allows for rapid and easy sequence determination of cyclic peptoids. The key idea in this strategy is a post-screening "ring-opening" reaction to convert cyclic peptoids selected from a high-throughput screen into linear peptoids, which can be sequenced by tandem mass spectrometry. Thus, there is no need for encoding.open113836sciescopu
Transient Multicomponent Mixture Analysis Based on an ICE Numerical Scheme for Predicting an Air Ingress Phenomena in a HTGR
No full textA chemical inhibitor of the Skp2/p300 interaction that promotes p53-mediated apoptosis
No full textSkp2 is thought to have two critical roles in tumorigenesis. As part of the SCFSkp2 ubiquitin ligase, Skp2 drives the cell cycle by mediating the degradation of cell cycle proteins. Besides the proteolytic activity, Skp2 also blocks p53-mediated apoptosis by outcompeting p53 for binding p300. Herein, we exploit the Skp2/p300 interaction as a new target for Skp2 inhibition. An affinity-based high-throughput screen of a combinatorial cyclic peptoid library identified an inhibitor that binds to Skp2 and interferes with the Skp2/p300 interaction. We show that antagonism of the Skp2/p300 interaction by the inhibitor leads to p300-mediated p53 acetylation, resulting in p53-mediated apoptosis in cancer cells, without affecting Skp2 proteolytic activity. Our results suggest that inhibition of the Skp2/p300 interaction has a great potential as a new anticancer strategy, and our Skp2 inhibitor can be developed as a chemical probe to delineate Skp2 non-proteolytic function in tumorigenesis.112015sciescopu
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