Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed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

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.