The development of highly potent and selective small molecule correctors of Z &#945;<sub>1</sub>-antitrypsin misfolding.

Liddle, John; Pearce, Andrew C; Arico-Muendel, Christopher; Belyanskaya, Svetlana; Brewster, Andrew; Brown, Murray; Chung, Chun-Wa; Denis, Alexis; Dodic, Nerina; Dossang, Anthony; Eddershaw, Peter; Klimaszewska, Diana; Haq, Imran; Holmes, Duncan S; Jagger, Alistair; Jakhria, Toral; Jigorel, Emilie; Lind, Ken; Messer, Jeff; Neu, Margaret; Olszewski, Allison; Ronzoni, Riccardo; Rowedder, James; Rüdiger, Martin; Skinner, Steve; Smith, Kathrine J; Trottet, Lionel; Uings, Iain; Zhu, Zhengrong; Irving, James A; Lomas, David A

The development of highly potent and selective small molecule correctors of Z α₁-antitrypsin misfolding.

Liddle, John; Pearce, Andrew C; Arico-Muendel, Christopher; Belyanskaya, Svetlana; Brewster, Andrew; Brown, Murray; Chung, Chun-Wa; Denis, Alexis; Dodic, Nerina; Dossang, Anthony; Eddershaw, Peter; Klimaszewska, Diana; Haq, Imran; Holmes, Duncan S; Jagger, Alistair; Jakhria, Toral; Jigorel, Emilie; Lind, Ken; Messer, Jeff; Neu, Margaret; Olszewski, Allison; Ronzoni, Riccardo; Rowedder, James; Rüdiger, Martin; Skinner, Steve; Smith, Kathrine J; Trottet, Lionel; Uings, Iain; Zhu, Zhengrong; Irving, James A; Lomas, David A.

Afiliación

Liddle J; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Pearce AC; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Arico-Muendel C; GlaxoSmithKline, Cambridge Park Drive, 6th Floor, Cambridge, MA 02140, USA.
Belyanskaya S; GlaxoSmithKline, Cambridge Park Drive, 6th Floor, Cambridge, MA 02140, USA.
Brewster A; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Brown M; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Chung CW; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Denis A; GlaxoSmithKline, Avenue du Quebec, Paris 91140, France.
Dodic N; GlaxoSmithKline, Avenue du Quebec, Paris 91140, France.
Dossang A; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Eddershaw P; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Klimaszewska D; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Haq I; UCL Respiratory, Rayne Institute, University College London, London WC1E 6JF, United Kingdom.
Holmes DS; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Jagger A; UCL Respiratory, Rayne Institute, University College London, London WC1E 6JF, United Kingdom.
Jakhria T; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Jigorel E; GlaxoSmithKline, Avenue du Quebec, Paris 91140, France.
Lind K; GlaxoSmithKline, Cambridge Park Drive, 6th Floor, Cambridge, MA 02140, USA.
Messer J; GlaxoSmithKline, Cambridge Park Drive, 6th Floor, Cambridge, MA 02140, USA.
Neu M; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Olszewski A; GlaxoSmithKline, Cambridge Park Drive, 6th Floor, Cambridge, MA 02140, USA.
Ronzoni R; UCL Respiratory, Rayne Institute, University College London, London WC1E 6JF, United Kingdom.
Rowedder J; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Rüdiger M; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Skinner S; GlaxoSmithKline, Cambridge Park Drive, 6th Floor, Cambridge, MA 02140, USA.
Smith KJ; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Trottet L; GlaxoSmithKline, Avenue du Quebec, Paris 91140, France.
Uings I; GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom.
Zhu Z; GlaxoSmithKline, Cambridge Park Drive, 6th Floor, Cambridge, MA 02140, USA.
Irving JA; UCL Respiratory, Rayne Institute, University College London, London WC1E 6JF, United Kingdom.
Lomas DA; UCL Respiratory, Rayne Institute, University College London, London WC1E 6JF, United Kingdom. Electronic address: d.lomas@ucl.ac.uk.

Bioorg Med Chem Lett ; 41: 127973, 2021 06 01.

Article en En | MEDLINE | ID: mdl-33753261

ABSTRACT

ABSTRACT

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.

Asunto(s)

Diseño de Fármacos; Pliegue de Proteína; alfa 1-Antitripsina/metabolismo; Cristalización; Desarrollo de Medicamentos/métodos; Evaluación Preclínica de Medicamentos; Retículo Endoplásmico/metabolismo; Biblioteca de Genes; Hepatocitos/metabolismo; Humanos; Modelos Moleculares; Conformación Proteica; alfa 1-Antitripsina/genética

Palabras clave

2-Oxindole; Misfolding; α1-Antitrypsin

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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Diseño de Fármacos / Alfa 1-Antitripsina / Pliegue de Proteína Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Reino Unido

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