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1.
Chem Commun (Camb) ; 47(6): 1827-9, 2011 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-21180730

RESUMO

The ligand bis(2-isobutyrylamidophenyl)amine has been prepared and used to stabilize both mononuclear and dinuclear cobalt(II) complexes. The nuclearity of the cobalt product is regulated by the deprotonation state of the ligand. Both complexes catalytically oxidize triphenylphosphine to triphenylphosphine oxide in the presence of O(2).

2.
PLoS One ; 5(5): e10504, 2010 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-20498699

RESUMO

BACKGROUND: Insulin is a vital peptide hormone that is a central regulator of glucose homeostasis, and impairments in insulin signaling cause diabetes mellitus. In principle, it should be possible to enhance the activity of insulin by inhibiting its catabolism, which is mediated primarily by insulin-degrading enzyme (IDE), a structurally and evolutionarily distinctive zinc-metalloprotease. Despite interest in pharmacological inhibition of IDE as an attractive anti-diabetic approach dating to the 1950s, potent and selective inhibitors of IDE have not yet emerged. METHODOLOGY/PRINCIPAL FINDINGS: We used a rational design approach based on analysis of combinatorial peptide mixtures and focused compound libraries to develop novel peptide hydroxamic acid inhibitors of IDE. The resulting compounds are approximately 10(6) times more potent than existing inhibitors, non-toxic, and surprisingly selective for IDE vis-à-vis conventional zinc-metalloproteases. Crystallographic analysis of an IDE-inhibitor complex reveals a novel mode of inhibition based on stabilization of IDE's "closed," inactive conformation. We show further that pharmacological inhibition of IDE potentiates insulin signaling by a mechanism involving reduced catabolism of internalized insulin. CONCLUSIONS/SIGNIFICANCE: The inhibitors we describe are the first to potently and selectively inhibit IDE or indeed any member of this atypical zinc-metalloprotease superfamily. The distinctive structure of IDE's active site, and the mode of action of our inhibitors, suggests that it may be possible to develop inhibitors that cross-react minimally with conventional zinc-metalloproteases. Significantly, our results reveal that insulin signaling is normally regulated by IDE activity not only extracellularly but also within cells, supporting the longstanding view that IDE inhibitors could hold therapeutic value for the treatment of diabetes.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Insulina/metabolismo , Insulisina/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Cristalografia por Raios X , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/química , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Células HeLa , Humanos , Insulisina/química , Modelos Moleculares , Biblioteca de Peptídeos , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
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