Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain

摘要

Systemic light chain amyloidosis is a disease that occurs when individuals produce too much of an immune protein. The excess protein chains normally exist in the body as individual molecules called “monomers” or in pairs called “dimers,” and they can readily switch between these two forms. However, the monomers are also prone to forming amyloid fibrils, which are difficult to break down. Amyloid fibrils are often deposited in the heart and kidneys and can lead to organ failure and death. Finding molecules that prevent the formation of amyloid fibrils could help to develop treatments for amyloidosis. Now, Brumshtein, Esswein et al. have screened 27 compounds to identify those that stabilize the dimer form of the protein. This would reduce the number of monomers in the body, and so reduce the number of immune proteins that can form amyloid fibrils. The experiments identified four compounds that could stabilize the dimers, including one called methylene blue. Comparing the chemical structures of these compounds with the structures of drugs approved for medical use identified thirteen drugs. However, follow-up tests showed that only one, called sulfasalazine, reduced the formation of amyloid fibrils. Neither methylene blue nor sulfasalazine is likely to have a strong enough effect to treat amyloidosis, but they may serve as templates for future drug designs.