rational design of inhibitors of gelsolin amyloid aggregation

Cancer is at times described as cells getting sick and going mad. Then amyloidosis is the sickness of proteins, which lose their normal shape and group together. These clamps of abnormally-shaped proteins grow over time, eventually forming long fibers that deposit in different organs, where they cause inflammation and mechanical damage. In Agel amyloidosis, the gelsolin protein inherits its sickness and the mutated protein is aberrantly chopped in small fragments. These small pieces recognize each other and self-assemble as a pile of identical LEGO bricks. Preventing this process would cure the disease. What if we could build a brick with the same top knobs as the gelsolin fragment but lacking the bottom tubes? Would this brick-mimic be able to dock but prevent addition of other blocks? To answer these questions, we recently crafted three such brick-mimics and indeed showed that two of them make the piling of gelsolin bricks less efficient. Based on these promising observations, we now plan to better understand how these mimics work and craft new ones that could better prevent the building process. To eventually test these bricks in a biological context we also plan to develop a small worm that expresses human gelsolin. This simplified animal model of the disease represents a step forward from bench to bedside.