Amyloid Composition and Structure-Based Development of Therapeutic and Diagnostic Agents

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 25 May 2025 | Viewed by 5303

Special Issue Editors


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Guest Editor
Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA
Interests: amyloidosis; diagnostics; early detection strategies

E-Mail Website
Guest Editor
Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA
Interests: amyloidosis; immunotherapy; imaging

Special Issue Information

Dear Colleagues,

The treatment and diagnosis of systemic amyloidosis is a constantly developing and important field. Despite remarkable advances in these areas over the last few years, there remain significant unmet clinical needs and improvements in clinical care that can be made, especially in the rarer forms of hereditary amyloidosis.

This Special Issue, entitled “Amyloid Composition and Structure-Based Development of Therapeutic and Diagnostic Agents”, seeks to provide a comprehensive collection of informative articles that describe the interrelationship between an understanding of the structure of amyloid and the development of clinically relevant therapeutics and diagnostics.

We cordially invite you to contribute an article to this volume as either original research, a mini review, or a clinical case study.

Topics of interest include structural studies of amyloid precursor proteins and amyloid fibrils and how this knowledge has or may inform the development of clinically relevant reagents, characterization of the composition of tissue amyloid and how this impacts the development of novel clinical agents, and descriptions of current and novel clinical reagents that rely on structural and compositional characteristics of amyloid for efficacy.

The aim of this Special Issue is to highlight diagnostic and therapeutic reagents that were developed, or may be developed, based on the composition of amyloid and the growing appreciation of the structure of amyloidogenic proteins and amyloid fibrils.

Dr. Emily B. Martin
Prof. Dr. Jonathan S. Wall
Guest Editors

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Published Papers (4 papers)

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Research

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19 pages, 5673 KiB  
Article
Exploring the Aβ Plaque Microenvironment in Alzheimer’s Disease Model Mice by Multimodal Lipid-Protein-Histology Imaging on a Benchtop Mass Spectrometer
by Elisabeth Müller, Thomas Enzlein, Dagmar Niemeyer, Livia von Ammon, Katherine Stumpo, Knut Biber, Corinna Klein and Carsten Hopf
Pharmaceuticals 2025, 18(2), 252; https://doi.org/10.3390/ph18020252 - 13 Feb 2025
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Abstract
Amyloid-β (Aβ) plaque deposits in the brain are a hallmark of Alzheimer’s disease (AD) neuropathology. Plaques consist of complex mixtures of peptides like Aβ1–42 and characteristic lipids such as gangliosides, and they are targeted by reactive microglia and astrocytes. Background: In pharmaceutical [...] Read more.
Amyloid-β (Aβ) plaque deposits in the brain are a hallmark of Alzheimer’s disease (AD) neuropathology. Plaques consist of complex mixtures of peptides like Aβ1–42 and characteristic lipids such as gangliosides, and they are targeted by reactive microglia and astrocytes. Background: In pharmaceutical research and development, it is a formidable challenge to contextualize the different biomolecular classes and cell types of the Aβ plaque microenvironment in a coherent experimental workflow on a single tissue section and on a benchtop imaging reader. Methods: Here, we developed a workflow that combines lipid MALDI mass spectrometry imaging using a vacuum-stable matrix with histopathology stains and with the MALDI HiPLEX immunohistochemistry of plaques and multiple protein markers on a benchtop imaging mass spectrometer. The three data layers consisting of lipids, protein markers, and histology could be co-registered and evaluated together. Results: Multimodal data analysis suggested the extensive co-localization of Aβ plaques with the peptide precursor protein, with a defined subset of lipids and with reactive glia cells on a single brain section in APPPS1 mice. Plaque-associated lipids like ganglioside GM2 and phosphatidylinositol PI38:4 isoforms were readily identified using the tandem MS capabilities of the mass spectrometer. Conclusions: Altogether, our data suggests that complex pathology involving multiple lipids, proteins and cell types can be interrogated by this spatial multiomics workflow on a user-friendly benchtop mass spectrometer. Full article
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23 pages, 3691 KiB  
Article
Predicting Structural Consequences of Antibody Light Chain N-Glycosylation in AL Amyloidosis
by Gareth J. Morgan, Zach Yung, Brian H. Spencer, Vaishali Sanchorawala and Tatiana Prokaeva
Pharmaceuticals 2024, 17(11), 1542; https://doi.org/10.3390/ph17111542 - 16 Nov 2024
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Abstract
Background/Objectives: Antibody light chains form amyloid fibrils that lead to progressive tissue damage in amyloid light chain (AL) amyloidosis. The properties of each patient’s unique light chain appear to determine its propensity to form amyloid. One factor is N-glycosylation, which is more frequent [...] Read more.
Background/Objectives: Antibody light chains form amyloid fibrils that lead to progressive tissue damage in amyloid light chain (AL) amyloidosis. The properties of each patient’s unique light chain appear to determine its propensity to form amyloid. One factor is N-glycosylation, which is more frequent in amyloid-associated light chains than in light chains from the normal immune repertoire. However, the mechanisms underlying this association are unknown. Here, we investigate the frequency and position within the light chain sequence of the N-glycosylation sequence motif, or sequon. Methods: Monoclonal light chains from AL amyloidosis and multiple myeloma were identified from the AL-Base repository. Polyclonal light chains were obtained from the Observed Antibody Space resource. We compared the fraction of light chains from each group harboring an N-glycosylation sequon, and the positions of these sequons within the sequences. Results: Sequons are enriched among AL-associated light chains derived from a subset of precursor germline genes. Sequons are observed at multiple positions, which differ between the two types of light chains, κ and λ, but are similar between light chains from AL amyloidosis and multiple myeloma. Positions of sequons map to residues with surface-exposed sidechains that are compatible with the folded structures of light chains. Within the known structures of λ AL amyloid fibrils, many residues where sequons are observed are buried, inconsistent with N-glycosylation. Conclusions: There is no clear structural rationale for why N-glycosylation of κ light chains is associated with AL amyloidosis. A better understanding of the roles of N-glycosylation in AL amyloidosis is required before it can be used as a marker for disease risk. Full article
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12 pages, 2033 KiB  
Article
Novel Ultrasound-Responsive Amyloid Formulation
by Maytham Ismail and Mathumai Kanapathipillai
Pharmaceuticals 2024, 17(6), 777; https://doi.org/10.3390/ph17060777 - 13 Jun 2024
Cited by 1 | Viewed by 1054
Abstract
Amyloid aggregates have attracted significant interest in regard to diverse biomedical applications, particularly in the field of drug delivery. Here, we report novel amyloid aggregates based on a 12-amino-acid peptide from the amyloidogenic region of the receptor-interacting kinase 3 (RIP3) protein and a [...] Read more.
Amyloid aggregates have attracted significant interest in regard to diverse biomedical applications, particularly in the field of drug delivery. Here, we report novel amyloid aggregates based on a 12-amino-acid peptide from the amyloidogenic region of the receptor-interacting kinase 3 (RIP3) protein and a thermoresponsive triblock copolymer, namely, Pluronic F127 (RIP3/F127). Physicochemical characterization was performed to determine the aggregation size, morphology, and stimuli-responsive properties. The potential of the aggregates as a drug depot was assessed in lung cancer cells, using Doxorubicin (Dox) as a model drug. The results show that RIP3 and RIP3/F127 exhibit amyloidogenic properties. Further, the RIP3/F127 amyloids exhibited significant ultrasound-responsive properties compared to amyloid aggregates without Pluronic F127. Moreover, the RIP3/F127/Dox amyloid formulations that were subjected to ultrasound treatment exhibited greater toxicity to lung cancer cells compared to that of Dox alone at equal concentrations. Overall, the results from this proof-of-concept study show that amyloidogenic peptide aggregates with stimuli-responsive properties can be utilized as efficient drug delivery depots. Full article
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13 pages, 1724 KiB  
Review
Structural Basis for Monoclonal Antibody Therapy for Transthyretin Amyloidosis
by Avi Chakrabartty
Pharmaceuticals 2024, 17(9), 1225; https://doi.org/10.3390/ph17091225 - 17 Sep 2024
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Abstract
The disease of transthyretin (TTR) amyloidosis (ATTR) has been known since the 1960s, and during the past 60 or so years, there has been a sustained period of steady discoveries that have led to the current model of ATTR pathogenesis. More recent research [...] Read more.
The disease of transthyretin (TTR) amyloidosis (ATTR) has been known since the 1960s, and during the past 60 or so years, there has been a sustained period of steady discoveries that have led to the current model of ATTR pathogenesis. More recent research has achieved major advances in both diagnostics and therapeutics for ATTR, which are having a significant impact on ATTR patients today. Aiding these recent achievements has been the remarkable ability of cryo-electron microscopy (EM) to determine high-resolution structures of amyloid fibrils obtained from individual patients. Here, we will examine the cryo-EM structures of transthyretin amyloid fibrils to explore the structural basis of the two monoclonal antibody therapies for ATTR that are in clinical trials, ALXN-2220 and Coramitug, as well as to point out potential applications of this approach to other systemic amyloid diseases. Full article
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