Identification of bioactive molecules for the treatment of 1-antitrypsin deficiency

Alpha-1-Antitrypsin is produced by the liver and bathes all the tissues of the body. The Z mutation is found in 4% of the Caucasian population. It causes the protein to undergo an abnormal conformational transition and form chains of polymers that are retained within hepatocytes. These retained polymers form inclusion bodies that damage the liver and give rise to liver disease that can affect children and adults. The only treatment for this condition is transplantation for those individuals with end-stage liver disease. The mechanism by which the protein accumulates within the liver cells has been elucidated by Professor Lomas‘ group in Cambridge. They have shown that the mutation causes the protein to change shape and form polymers. They have identified a cavity on the surface of the protein and have collaborated with Professor Abagyan (Scripps Research Institute, USA) to screen >1,170,000 compounds for small molecules that can fill this cavity. When they have looked in more detail they have found that six of the compounds were able to bind to this cavity and block polymerisation. I now propose to refine their lead compounds to identify other bioactive drugs that may be developed as novel therapies for alpha-1-antitrypsin deficiency.

Prof Lomas‘ group (University of Cambridge, UK) have shown 1-antitrypsin deficiency results from polymerisation of mutant protein within the endoplasmic reticulum of hepatocytes. They have collaborated with Prof. Abagyan‘s group (Scripps Research Institute, USA) to identify small molecules that can block the conformational transition that underlies 1-antitrypsin deficiency. I propose to capitalise on this collaboration to: (i) undertake computational analysis to refine the lead compounds in order to define small molecules that are more potent in inhibiting the polymerisation of Z 1-antitrypsin; (ii) assess the effect of these refined compounds on the stability and structure of Z 1-antitrypsin; (iii) assess the effect of the refined compounds on the inhibitory kinetics of Z 1-antitrypsin with neutrophil elastase; (iv) determine the KD for binding of the refined compounds to Z 1-antitrypsin; (v) determine the crystal structure of the refined compounds bound to Z 1-antitrypsin and (vi) assess whether the most effective of the small molecules increases the secretion of Z 1-antitrypsin in cell models of disease. These data will then allow refinement of the lead compound to develop a novel drug to block the polymerisation of Z 1-antitrypsin in vitro and in vivo. Such an approach may form the basis for a ‘cure‘ for the protein overload and liver disease that are associated with the Z allele of 1-antitrypsin.