Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis

Gareth J Morgan

doi:10.3390/molecules26123571

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. 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.

Highlights

Deposition of amyloid fibrils derived from antibody light-chain (LC) proteins is associated with organ damage in the disease amyloid light-chain (AL) amyloidosis [1,2]
Inhibition of amyloid fibril formation is challenging, and it is perhaps surprising that so many small molecules have been reported to inhibit the amyloidogenesis of several proteins in vitro or have shown efficacy in clinical trials
Such observations with natural products or drugs approved for other indications raise the possibility that more efficacious inhibitors of amyloidogenesis could be developed

Summary

Introduction

Deposition of amyloid fibrils derived from antibody light-chain (LC) proteins is associated with organ damage in the disease amyloid light-chain (AL) amyloidosis [1,2]. AL amyloidosis is the most commonly diagnosed form of “systemic” amyloidosis, where amyloid fibrils form in multiple tissues [3]. In these diseases, amyloid fibrils are closely associated with pathology, and inhibition of amyloid deposition by suppression or stabilization of the precursor protein can lead to clinical benefits [4]. LCs are ~215-residue proteins that form two structural immunoglobulin domains. LCs can form homodimers, which may be stabilized by an inter-chain disulfide bond between the CL-domains

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