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
A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 1012 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed.