RESUMO
α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors.
Assuntos
Desenho de Fármacos , Dobramento de Proteína , alfa 1-Antitripsina/metabolismo , Cristalização , Desenvolvimento de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Retículo Endoplasmático/metabolismo , Biblioteca Gênica , Hepatócitos/metabolismo , Humanos , Modelos Moleculares , Conformação Proteica , alfa 1-Antitripsina/genéticaRESUMO
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.