| Autor: |
Stefan J. Marciniak, Martin Rüdiger, Hitesh Dave, Jonathan P. Hutchinson, Margaret Neu, Anthony Dossang, Riccardo Ronzoni, Lionel Trottet, Adriana Ordóñez, Chun-wa Chung, Christopher C. Arico-Muendel, Alexis Denis, Allison Olszewski, Andrew C. Pearce, Ken Lind, Peter Eddershaw, Andrew Brewster, Rebecca Terry, Jeffrey A. Messer, John Liddle, Iain Uings, Emilie Jigorel, James A. Irving, Nerina Dodic, Zhengrong Zhu, Kathrine J. Smith, Duncan S. Holmes, Steve Skinner, Steve Wilson, David A. Lomas, Diana Klimaszewska, James E. Rowedder, Murray J. B. Brown, Alistair M. Jagger, Toral Jakhria, Imran Haq, Svetlana L. Belyanskaya |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
Severe α1-antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1-antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high throughput screen to identify small molecules that bind to, and stabilise Z α1-antitrypsin. The lead compound blocks Z α1-antitrypsin polymerisationin vitro, reduces intracellular polymerisation and increases the secretion of Z α1-antitrypsin three-fold in mammalian cells including an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerization pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1-antitrypsin into the plasma by 7-fold. There was no observable clearance of hepatic inclusions with respect to controls. This study provides proof-of-principle that ‘mutation ameliorating’ small molecules are a viable approach to treat protein conformational diseases. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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