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

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 polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1 -antitrypsin threefold in 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 polymerisation 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 sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that "mutation ameliorating" small molecules can block the aberrant polymerisation that underlies Z α1 -antitrypsin deficiency.

Myelin growth and initial dynamics.

During the dissolution of solid surfactants in water, various types of nonequilibrium microstructures have been observed. The most important one is the myelin growth which can be observed when some poorly water soluble surfactants such as phosphatidylcholine (PC), Aerosol-OT (AOT), etc. are contacted with water. In this study initial myelin growth for a period of 2-4 s is studied both qualitatively as well as quantitatively in all the directions with respect to water flow in a PC system using digital video microscopy. Further, overall myelin growth is studied by means of optical microscopy to understand the effect of distance between cover slip and glass slide on myelin growth. Experiments are also performed to study effect of additives (silica) to lamellar phase on diffusion coefficients. It has been observed that the presence of silica particles causes extensive coiling of myelin structures. The mechanism of water transport into the lamellar phase during myelin growth is investigated by using silica in a colloidal range as dopant material.