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dc.contributor.authorMorgan, Gareth Johnen_US
dc.date.accessioned2021-08-20T12:19:35Z
dc.date.available2021-08-20T12:19:35Z
dc.date.issued2021-06-11
dc.identifier.citationMorgan, G.J. Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis. Molecules 2021, 26, 3571. https://doi.org/10.3390/molecules26123571
dc.identifier.urihttps://hdl.handle.net/2144/42923
dc.description.abstractInhibition 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.en_US
dc.language.isoen_US
dc.publisherMDPIen_US
dc.rightsCopyright: © 2021 by the author. This is an open access article distributed under the Creative Commons Attribution (CC-BY) License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0
dc.subjectSystemic amyloidosisen_US
dc.subjectAmyloid fibrilsen_US
dc.subjectAmyloidogenesis inhibitorsen_US
dc.subjectAntibody light chainsen_US
dc.subjectLight-chain stabilizersen_US
dc.titleBarriers to small molecule drug discovery for systemic amyloidosisen_US
dc.typeArticleen_US
dc.identifier.doi10.3390/molecules26123571
dc.identifier.orcid0000-0002-1275-2010


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Copyright: © 2021 by the author. This is an open access article distributed under the Creative Commons Attribution (CC-BY) License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as Copyright: © 2021 by the author. This is an open access article distributed under the Creative Commons Attribution (CC-BY) License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.