Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.26.217661v1?rss=1 Authors: Lomas, D., Irving, J. A., Arico-Muendel, C., Belyanskaya, S., Brewster, A., Brown, M. J. B., Chung, C.-w., Dave, H., Denis, A., Dodic, N., Dossang, A., Eddershaw, P., Klimaszewska, D., Haq, I., Holmes, D., Hutchinson, J., Jagger, A. M., Jakhria, T., Jigorel, E., Liddle, J., Lind, K., Marciniak, S. J., Messer, J., Neu, M., Olszewski, A., Ordonez, A., Ronzoni, R., Rowedder, J., Rüdiger, M., Skinner, S., Smith, K., Terry, R., Trottet, L., Uings, I., Wilson, S., Zhu, Z., Pearce, A. C. Abstract: Severe 1-antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant 1-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 1-antitrypsin. The lead compound blocks Z 1-antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z 1-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 1-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. Copy rights belong to original authors. Visit the link for more info