RESUMO
In Huntington disease, polyglutamine expansion of the protein huntingtin (Htt) leads to selective neurodegenerative loss of medium spiny neurons throughout the striatum by an unknown apoptotic mechanism. Binding of Hip-1, a protein normally associated with Htt, is reduced by polyglutamine expansion. Free Hip-1 binds to a hitherto unknown polypeptide, Hippi (Hip-1 protein interactor), which has partial sequence homology to Hip-1 and similar tissue and subcellular distribution. The availability of free Hip-1 is modulated by polyglutamine length within Htt, with disease-associated polyglutamine expansion favouring the formation of pro-apoptotic Hippi-Hip-1 heterodimers. This heterodimer can recruit procaspase-8 into a complex of Hippi, Hip-1 and procaspase-8, and launch apoptosis through components of the 'extrinsic' cell-death pathway. We propose that Htt polyglutamine expansion liberates Hip-1 so that it can form a caspase-8 recruitment complex with Hippi. This novel non-receptor-mediated pathway for activating caspase-8 might contribute to neuronal death in Huntington disease.
Assuntos
Proteínas de Transporte/metabolismo , Caspases/metabolismo , Proteínas de Ligação a DNA , Doença de Huntington/metabolismo , Neurônios/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Animais , Apoptose/fisiologia , Proteínas de Transporte/genética , Caspase 8 , Caspase 9 , Caspases/genética , Células Cultivadas , Ativação Enzimática , Humanos , Proteína Huntingtina , Doença de Huntington/enzimologia , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/ultraestrutura , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Estrutura Terciária de Proteína , Ratos , Alinhamento de Sequência , Distribuição Tecidual , Técnicas do Sistema de Duplo-HíbridoRESUMO
Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact on the treatment of several degenerative diseases. Here we report the synthesis of reversible inhibitors via a solid-support palladium-catalyzed amination of 3-bromopyrazinones and the discovery of a pan-caspase reversible inhibitor.
Assuntos
Inibidores de Caspase , Paládio/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Aminação , Catálise , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Humanos , Indicadores e Reagentes , Espectrometria de Massas , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
The iterative process for the discovery of a series of pyrazinone mono-amides as potent, selective and reversible non-peptide caspase-3 inhibitors (e.g., M826 and M867) is reported. These compounds display potent anti apoptotic activities in a number of cell based systems in vitro as well as in several animal models in vivo.
Assuntos
Amidas/síntese química , Inibidores de Caspase , Amidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3 , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Leucócitos/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Pirazinas/síntese química , Pirazinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Caspase 3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. The P1 aspartic acid residue is a required element of recognition for this enzyme that was maintained constant along with the adjacent natural valine as the P2 group. The thiobenzylmethylketone warhead on the aspartate was conveniently handled through solid-phase synthesis allowing modification in the P3 region that eventually led to simpler derivatives with increased potency against caspase 3. The key to such an effect is the introduction of hydroxyl group alpha to the P3 carbonyl.
Assuntos
Inibidores de Caspase , Dipeptídeos/síntese química , Cetonas/síntese química , Ácido Aspártico , Caspase 3 , Técnicas de Química Combinatória , Dipeptídeos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Cetonas/farmacologia , Proteínas Recombinantes , Relação Estrutura-Atividade , ValinaRESUMO
A robust method for the solid phase synthesis of a series of selective caspase-3 peptide inhibitors is described. The inhibitors can be obtained after cleavage from the solid support without further purification.
Assuntos
Inibidores de Caspase , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Caspase 3 , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Combinatória , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50RESUMO
The discovery of a series of potent, selective and reversible dipeptidyl caspase-3 inhibitors are reported. The iterative discovery process of using combinatorial chemistry, parallel synthesis, moleculare modelling and structural biology will be discussed.
Assuntos
Ácido Aspártico/química , Inibidores de Caspase , Dipeptídeos , Inibidores Enzimáticos , Cetonas , Sítios de Ligação , Caspase 3 , Células Cultivadas , Técnicas de Química Combinatória , Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Cetonas/síntese química , Cetonas/farmacologia , Modelos Moleculares , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. Since P(1) aspartic acid is a required element of recognition for this enzyme, a library of capped aspartyl aldehydes was synthesized using solid-phase chemistry. The 5-bromonicotinamide derivative of the aspartic acid aldehyde was identified to be an inhibitor of caspase-3. Substitution at the 5-position of the pyridine ring and conversion of the aldehyde to ketones led to a series of potent inhibitors of caspase-3.