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Bioorg Med Chem Lett
; 29(20): 126675, 2019 10 15.
Artigo
em Inglês
| MEDLINE
| ID: mdl-31521475
RESUMO
The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.
Assuntos
Benzamidinas/química , Calicreínas/antagonistas & inibidores , Síndrome de Netherton/tratamento farmacológico , Inibidores de Serina Proteinase/química , Sequência de Aminoácidos , Benzamidinas/farmacologia , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Humanos , Isomerismo , Modelos Moleculares , Estrutura Molecular , Mutação , Ligação Proteica , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade
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