Assuntos
Reprogramação Celular , Células-Tronco Pluripotentes Induzidas/citologia , Inibidores de Proteínas Quinases/química , Fatores de Transcrição SOXB1/metabolismo , Quinases da Família src/antagonistas & inibidores , Animais , Dasatinibe , Doxiciclina/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Fatores de Transcrição SOXB1/genética , Tiazóis/química , Tiazóis/farmacologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo , Quinases da Família src/genética , Quinases da Família src/metabolismoRESUMO
Ectopic expression of defined transcription factors can reprogram somatic cells to induced pluripotent stem (iPS) cells, but the utility of iPS cells is hampered by the use of viral delivery systems. Small molecules offer an alternative to replace virally transduced transcription factors with chemical signaling cues responsible for reprogramming. In this report we describe a small-molecule screening platform applied to identify compounds that functionally replace the reprogramming factor Klf4. A series of small-molecule scaffolds were identified that activate Nanog expression in mouse fibroblasts transduced with a subset of reprogramming factors lacking Klf4. Application of one such molecule, kenpaullone, in lieu of Klf4 gave rise to iPS cells that are indistinguishable from murine embryonic stem cells. This experimental platform can be used to screen large chemical libraries in search of novel compounds to replace the reprogramming factors that induce pluripotency. Ultimately, such compounds may provide mechanistic insight into the reprogramming process.
Assuntos
Benzazepinas/farmacologia , Diferenciação Celular , Epigênese Genética/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Indóis/farmacologia , Células-Tronco Pluripotentes/citologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Fibroblastos/citologia , Genes Reporter , Proteínas de Homeodomínio/genética , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Luciferases/genética , Camundongos , Proteína Homeobox NanogRESUMO
This report presents an overview of the family of naturally occurring 'vinylic' amino acids, namely those that feature a C-C double bond directly attached to the α-carbon, along the side chain. Strategies that have been brought to bear on the stereocontrolled synthesis of these olefinic amino acids are surveyed. The mechanistic diversity by which such 'vinylic triggers' can be actuated in a PLP (pyridoxal phosphate) enzyme active site is then highlighted by discussions of vinylglycine (VG), its substituted congeners, particularly AVG [4E-(2'-aminoethoxy)vinylglycine], and a naturally occurring VG-progenitor, SMM (S-methylmethionine).
RESUMO
[reaction: see text] Mannose 6-phosphate mimics locked into the alpha-configuration and bearing hydrolase-resistant phosphate surrogates were synthesized and evaluated for binding affinity to the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R). Affinity increases as the phosphate surrogate is varied in the order malonyl ether < malonate < phosphonate. An alkene cross-metathesis approach to sought-after bivalent M6P-bearing ligands is also described. These compounds were designed to map onto biantennary sectors of high-mannose-type oligosaccharides carried by glycoprotein M6P/IGF2R ligands.
