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1.
J Med Chem ; 63(8): 4107-4116, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32202781

RESUMO

Bicycles are constrained bicyclic peptides that represent a promising binding modality for use in targeted drug conjugates. A phage display screen against EphA2, a receptor tyrosine kinase highly expressed in a number of solid tumors, identified a number of Bicycle families with low nanomolar affinity. A Bicycle toxin conjugate (BTC) was generated by derivatization of one of these Bicycles with the potent cytotoxin DM1 via a cleavable linker. This BTC demonstrated potent antitumor activity in vivo but was poorly tolerated, which was hypothesized to be the result of undesired liver uptake caused by poor physicochemical properties. Chemical optimization of a second Bicycle, guided by structural biology, provided a high affinity, metabolically stable Bicycle with improved physicochemical properties. A BTC incorporating this Bicycle also demonstrated potent antitumor activity and was very well tolerated when compared to the initial BTC. Phage display selection followed by chemical optimization of Bicycles can deliver potent drug conjugates with favorable pharmaceutical properties.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Citotoxinas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Efrina-A2/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Citotoxinas/química , Citotoxinas/metabolismo , Efrina-A2/metabolismo , Feminino , Humanos , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptor EphA2 , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
2.
Nature ; 416(6881): 636-40, 2002 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-11948352

RESUMO

The inability of axons to regenerate after a spinal cord injury in the adult mammalian central nervous system (CNS) can lead to permanent paralysis. At sites of CNS injury, a glial scar develops, containing extracellular matrix molecules including chondroitin sulphate proteoglycans (CSPGs). CSPGs are inhibitory to axon growth in vitro, and regenerating axons stop at CSPG-rich regions in vivo. Removing CSPG glycosaminoglycan (GAG) chains attenuates CSPG inhibitory activity. To test the functional effects of degrading chondroitin sulphate (CS)-GAG after spinal cord injury, we delivered chondroitinase ABC (ChABC) to the lesioned dorsal columns of adult rats. We show that intrathecal treatment with ChABC degraded CS-GAG at the injury site, upregulated a regeneration-associated protein in injured neurons, and promoted regeneration of both ascending sensory projections and descending corticospinal tract axons. ChABC treatment also restored post-synaptic activity below the lesion after electrical stimulation of corticospinal neurons, and promoted functional recovery of locomotor and proprioceptive behaviours. Our results demonstrate that CSPGs are important inhibitory molecules in vivo and suggest that their manipulation will be useful for treatment of human spinal injuries.


Assuntos
Condroitina ABC Liase/metabolismo , Condroitina ABC Liase/uso terapêutico , Regeneração Nervosa/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Animais , Axônios/metabolismo , Axônios/patologia , Eletrofisiologia , Proteína GAP-43/metabolismo , Gânglios Espinais/lesões , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Humanos , Isoenzimas/metabolismo , Masculino , Atividade Motora , Compressão Nervosa , Neurônios/metabolismo , Neurônios/patologia , Proteína Quinase C/metabolismo , Desempenho Psicomotor , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Regulação para Cima
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