Development of a small molecule that corrects misfolding and increases secretion of Z α1‐antitrypsin

Autor: David A Lomas, James A Irving, Christopher Arico‐Muendel, Svetlana Belyanskaya, Andrew Brewster, Murray Brown, Chun‐wa Chung, Hitesh Dave, Alexis Denis, Nerina Dodic, Anthony Dossang, Peter Eddershaw, Diana Klimaszewska, Imran Haq, Duncan S Holmes, Jonathan P Hutchinson, Alistair M Jagger, Toral Jakhria, Emilie Jigorel, John Liddle, Ken Lind, Stefan J Marciniak, Jeff Messer, Margaret Neu, Allison Olszewski, Adriana Ordonez, Riccardo Ronzoni, James Rowedder, Martin Rüdiger, Steve Skinner, Kathrine J Smith, Rebecca Terry, Lionel Trottet, Iain Uings, Steve Wilson, Zhengrong Zhu, Andrew C Pearce

Publikováno v: EMBO Molecular Medicine, Vol 13, Iss 3, Pp 1-16 (2021)

Abstract 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 use

Externí odkaz: https://doaj.org/article/73075a476ae1421891a994ecbcb35e20

Assessment of the safety, pharmacokinetics and pharmacodynamics of GSK3335065, an inhibitor of kynurenine monooxygenase, in a randomised placebo‐controlled first‐in‐human study in healthy volunteers

Autor: Catherine Muya, Sara Soleman, Alexander W. Krug, Sarah Walsh, Xinyi Zhu, Nicola Robertson, Richard J. Dimelow, William J. Guiney, Madelein Crause, Disala Fernando, Iain Uings, Georgios Vlasakakis, Marylise Bergeal, Wayne L. Wright, Yi Cui, Connie Parker, Ciara Gorey

Publikováno v: British Journal of Clinical Pharmacology. 88:865-870

GSK3335065 is an inhibitor of kynurenine monooxygenase (KMO) being developed for the treatment of acute pancreatitis. Healthy male volunteers were administered ascending doses of GSK3335065 or matched placebo as a single intravenous bolus injection t

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7a33ecb7f572aef6fad5cd2778c8950f
https://doi.org/10.1111/bcp.15010

Molecular Patterns in Acute Pancreatitis Reflect Generalizable Endotypes of the Host Response to Systemic Injury in Humans

Autor: Michael U. Gutmann, Lucile Neyton, Craig Marshall, Damian J. Mole, Lisa-Marie Wilson, Christos Skouras, Andrea Doeschl-Wilson, Francesco V. Rao, J Kenneth Baillie, Xiaozhong Zheng, Iain Uings, Armel Nicolas

Publikováno v: Neyton, L P A, Zheng, X, Skouras, C, Doeschl-Wilson, A, Gutmann, M, Uings, I J, Rao, F V, Nicolas, A, Marshall, C, Wilson, L-M, Baillie, K & Mole, D 2020, ' Molecular patterns in acute pancreatitis reflect generalisable endotypes of the host response to systemic injury in humans ', Annals of Surgery, vol. n/a, no. n/a, n/a . https://doi.org/10.1097/SLA.0000000000003974

Objective: Acute Pancreatitis (AP) is sudden onset pancreas inflammation that causes systemic injury with a wide and markedly heterogeneous range of clinical consequences. Here, we hypothesised that this observed clinical diversity corresponds to div

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::05517363a7ad1ef1cd6a58bc002b5647
https://doi.org/10.1097/sla.0000000000003974

Development of a small molecule that corrects misfolding and increases secretion of Z α1-antitrypsin

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

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-encod

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_________::af5dc4b6dd1fbecffcf82db1f278226c
https://doi.org/10.1101/2020.07.26.217661

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

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

Publikováno v: Bioorganic & Medicinal Chemistry Letters. 41:127973

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 iden

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_________::6d246fffa8ad97002689f34f62901b59
https://doi.org/10.1016/j.bmcl.2021.127973