Article
Version 1
Preserved in Portico This version is not peer-reviewed
Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis
Version 1
: Received: 8 April 2021 / Approved: 9 April 2021 / Online: 9 April 2021 (15:07:24 CEST)
A peer-reviewed article of this Preprint also exists.
Morgan, G.J. Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis. Molecules 2021, 26, 3571. Morgan, G.J. Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis. Molecules 2021, 26, 3571.
Abstract
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. Although many small molecules have been proposed as inhibitors of amyloid formation, few have been successful in clinical trials. Amyloid formation is complex and several individual steps could be targeted by small molecules. 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 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 amyloidogenesis.
Keywords
Systemic amyloidosis; amyloid fibrils; amyloidogenesis inhibitors; antibody light chains; light chain stabilizers; doxycycline; EGCG; thioflavin T; filter trap; PAINS
Subject
Chemistry and Materials Science, Analytical Chemistry
Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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