Journal
MOLECULES
Volume 26, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/molecules26123571
Keywords
systemic amyloidosis; amyloid fibrils; amyloidogenesis inhibitors; antibody light chains; light-chain stabilizers; doxycycline; EGCG; thioflavin T; filter trap; PAINS
Funding
- Charles J. Brown Amyloid Center Research Fund of the Amyloidosis Center, Boston University School of Medicine
Ask authors/readers for more resources
Inhibition of amyloid fibril formation is important for systemic amyloidosis patients, but developing effective molecules faces challenges due to lack of understanding in their mechanisms of action. Different aspects of amyloidosis can be targeted with potential small molecule inhibitors, but it is difficult to find molecules that can effectively inhibit aggregation of precursor proteins for amyloidosis.
Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Amyloid formation is a complex process, where several individual steps could be targeted. Several small molecules have been proposed as inhibitors of amyloid formation. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light-chain dimers, the precursor proteins for amyloid light-chain (AL) amyloidosis, are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidosis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available