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The pathogenesis of amyloid fibrils. Abbreviations: SAA, serum amyloid A; IL-1, interleukin-1; IL-6, interleukin 6; TNF-α, tumour necrosis factor alpha; GAG, glycosaminoglycan; SAP, serum amyloid P.
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Secondary (AA) amyloidosis is a multisystem disorder complicating chronic infections or inflammatory diseases. It is characterized by extracellular deposit of fibrils composed of fragments of serum amyloid A (SAA), an acute phase reactant protein. The kidney is the most frequent organ involved, manifesting as progressive proteinuria and renal impai...
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Streszczenie Amyloidoza nerek jest jedną z najczęstszych i najcięższych manifestacji amyloidozy układowej. Do odkładania amyloidu w nerkach dochodzi prawie w każdej postaci amyloidozy, dlatego często pierwszym objawem choroby jest białkomocz lub obniżenie filtracji kłębuszkowej. Zajęcie nerek, obok amyloidozy serca, decyduje o rokowaniu chorego. Na...
Citations
... However, not all AA patients are responsive to these treatments [15,16] and other therapeutic strategies have been explored, such as blocking the interactions between SAA, or amyloid fibrils, and glycosaminoglycans [17,18]. Yet, clinical trials with the respective pharmacological agents did not result in a market approval [19][20][21]. ...
Background:
Systemic AA amyloidosis is a world-wide occurring protein misfolding disease in humans and animals that arises from the formation of amyloid fibrils from serum amyloid A (SAA) protein and their deposition in multiple organs.
Objective:
To identify new agents that prevent fibril formation from SAA protein and to determine their mode of action.
Materials and methods:
We used a cell model for the formation of amyloid deposits from SAA protein to screen a library of peptides and small proteins, which were purified from human hemofiltrate. To clarify the inhibitory mechanism the obtained inhibitors were characterised in cell-free fibril formation assays and other biochemical methods.
Results:
We identified lysozyme as an inhibitor of SAA fibril formation. Lysozyme antagonised fibril formation both in the cell model as well as in cell-free fibril formation assays. The protein binds SAA with a dissociation constant of 16.5 ± 0.6 µM, while the binding site on SAA is formed by segments of positively charged amino acids.
Conclusion:
Our data imply that lysozyme acts in a chaperone-like fashion and prevents the aggregation of SAA protein through direct, physical interactions.
... Eprodisate, thought to prevent amyloid deposition by directly targeting glycosaminoglycan-amyloid fibril complexes, 61 initially showed promise after demonstrating superiority to placebo in AA-amyloid kidney disease in a composite outcome of kidney function and/or death. 62 Unfortunately, a follow-up phase 3 clinical trial 63 did not meet its primary outcome of preserved kidney function, and further studies targeting this pathway are ongoing. In addition, efforts to target amyloidogenic precursor proteins (specifically their interaction with glycosaminoglycans) 64 are also in development. ...
Serum amyloid A protein (AA) amyloidosis, also known as secondary amyloidosis, is a known consequence of chronic inflammation and results from several conditions including inflammatory arthritis, periodic fever syndromes and chronic infection. AA amyloidosis can lead to multi-organ dysfunction, including changes to glomerular filtration rate (GFR) and proteinuria. Definitive diagnosis requires tissue biopsy, and management of AA amyloid kidney disease is primarily focused on treating the underlying inflammatory condition to stabilize GFR, reduce proteinuria and slow potential progression to kidney failure. In this narrative review, we describe the causes, pathophysiology, presentation and pathological diagnosis of AA amyloid kidney disease using an illustrative case of biopsy-proven AA amyloid kidney disease in a patient with long-standing rheumatoid arthritis who had a favorable response to IL-6 inhibition. We conclude the review with a description of established and more novel therapies for AA amyloidosis including published cases of use of tocilizumab (an IL-6 inhibitor) in biopsy-proven AA amyloid kidney disease.
... In a multicenter, randomized, double-blind, placebo controlled trial, Dember et al. demonstrated that eprodisate slowed the decline of renal function in AA amyloidosis patients [27]. The results from the second Phase III study will help determine whether eprosidate will become one of the new treatment approaches in fighting renal AA amyloidosis [28]. ...
... Eprodisate 51 was evaluated to protect renal function in patients with AA amyloidosis. It inhibits the polymerization of amyloid fibrils and the deposition of the fibrils in tissues by antagonizing the interactions between amyloidogenic proteins and GAGs [218]. Suramin 52 is aryl-sulfonate derivative that is clinically used in the treatment of first-stage African trypanosomiasis (sleeping sickness) caused by Trypanosoma brucei without CNS involvement [219]. ...
Glycosaminoglycans (GAGs) are very complex, natural anionic polysaccharides. They are polymers of repeating disaccharide units of uronic acid and hexosamine residues. Owing to their template-free, spatiotemporally controlled, and enzyme-mediated biosyntheses, GAGs possess enormous polydispersity, heterogeneity, and structural diversity which often translate into multiple biological roles. It is well documented that GAGs contribute to physiological and pathological processes by binding to proteins including serine proteases, serpins, chemokines, growth factors, and microbial proteins. Despite advances in the GAG field, the GAG-protein interface remains largely unexploited by drug discovery programs. Thus, non-saccharide glycosaminoglycan mimetics (NSGMs) have been rationally developed as a novel class of sulfated molecules that modulate GAG-protein interface to promote various biological outcomes of substantial benefit to human health. In this review, we describe the chemical, biochemical, and pharmacological aspects of recently reported NSGMs and highlight their therapeutic potentials as structurally and mechanistically novel anti-coagulants, anti-cancer agents, anti-emphysema agents, and anti-viral agents. We also describe the challenges that complicate their advancement and describe ongoing efforts to overcome these challenges with the aim of advancing the novel platform of NSGMs to clinical use.
... Perhaps surprisingly, there was no significant difference in terms of overall changes in proteinuria. Despite these encouraging results there was concern that some of the apparent drug benefit reflected a poor outcome in the subgroup of placebo patients who had nephrotic range proteinuria at baseline and the US and European regulatory bodies requested a confirmatory second Phase III trial which is ongoing [211]. ...
BACKGROUND: Amyloidosis is a disorder arising from the variable physiological effects of dysregulated, extracellular protein deposition. There are >30 different subtypes, all possessing the same histological characteristics and the two major organs affected are the kidneys and the heart. AIMS AND HYPOTHESIS: To evaluate current UK histological practices leading to a misdiagnosis of amyloidosis; To establish proteomics as a new diagnostic technique for identifying amyloid, in the UK; To investigate the usefulness of a relatively new biomarker i.e. Retinol Binding Protein (RBP), across amyloid subtypes and correlate values with biopsy findings, which has not previously been done; To identify the cause of death in patients with Stage III/ IV cardiac amyloidosis using, for the first time, Implantable Loop Recorders; To present the first comprehensive review of Light Chain Deposition Disease highlighting the relationship between haematological response and overall prognosis. RESULTS: In 65% of cases where renal amyloidosis was misdiagnosed as minimal change disease, Congo red staining was not undertaken and in 35% of cases neither Congo red staining, with cross-polarised light visualisation, nor electron microscopy was undertaken. Proteomics has now been established as a specific and sensitive technique by which to diagnose amyloid and the subtype, demonstrated by distinguishing Fibrinogen Aα-Chain (AFib) renal biopsies from other subtypes. Urinary RBP/Creatinine (RCR) correlated with the: degree of tubular atrophy, number of light chains, eGFR, presence of glycosuria and degree of tubular phosphate reabsorption. RCR values were especially high in AFib and AA amyloidosis. Pulseless Electrical Activity was identified as the terminal rhythm in patients with Stage III/IV cardiac amyloidosis and this was preceded by a high degree AV block. Deep clonal responses to chemotherapy are associated with improved renal and overall outcomes in LCDD and should be pursued even in advanced chronic kidney disease.
... In order to design drugs as therapy to halt the pro-amyloid cascades it is essential to understand the interaction of amyloidogenic proteins with partners in circulation such as GAGs. Based on previous studies, novel negative molecules are being tested in order to inhibit the binding of misfolded proteins to GAGs and thereby these agents could be appropriate to avoid the retention and deposition of fibrillar aggregates in tissues [30]. These studies involve sulfate groups with different efficiency either in vivo or in vitro models, and could be new strategies to inhibit the pathological aggregation of amyloid proteins. ...
Among other components of the extracellular matrix (ECM), glycoproteins and glycosaminoglycans (GAGs) have been strongly associated to the retention or misfolding of different proteins inducing the formation of deposits in amyloid diseases. The composition of these molecules is highly diverse and a key issue seems to be the equilibrium between physiological and pathological events. In order to have a model in which the composition of the matrix could be finely controlled, we designed and synthesized crosslinked hydrophilic polymers, the so-called hydrogels varying the amounts of negative charges and hydroxyl groups that are prevalent in GAGs. We checked and compared by fluorescence techniques the binding of human apolipoprotein A-I and a natural mutant involved in amyloidosis to the hydrogel scaffolds. Our results indicate that both proteins are highly retained as long as the negative charge increases, and in addition it was shown that the mutant is more retained than the Wt, indicating that the retention of specific proteins in the ECM could be part of the pathogenicity. These results show the importance of the use of these polymers as a model to get deep insight into the studies of proteins within macromolecules.
... 62 Sulfated small molecules have been constructed from commercially available starting materials to avoid the heterogeneity implicit in using naturally occurring GAGs and GAG fragments (Fig. 4). GAG mimetics such as 3-amino-1-propanesulfonic acid (3) 63 and eprodisate disodium (4) 64 have been tested as anti-amyloid agents for the treatment of Alzheimer's disease and amyloidosis. Polysulfonated compounds such as suramin (5), 65 poly(sodium-4-styrene sulfonate) (6), 66 and sulfonate polymers have been tested as well. ...
Heparin and heparan sulfate glycosaminoglycans are long, linear polysaccharides that are made up of alternating dissacharide sequences of highly sulfated uronic acid and amino sugars. Unlike heparin, which is only found in mast cells, heparan sulfate is ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These negatively-charged carbohydrate chains play essential roles in important cellular functions such as cell growth, adhesion, angiogenesis, and blood coagulation. However, these biomolecules are also involved in pathophysiological conditions such as pathogen infection and human disease. This review discusses past and current methods for targeting these complex biomolecules as a novel therapeutic strategy to treating disorders such as cancer, neurodegenerative diseases, and infection.
... [33][34][35] In addition, sulfonated molecules such as 3-amino-1propanesulfonic acid and 1,3-propanedisulfonic acid have been shown to be effective inhibitors of Aβ and serum amyloid A aggregation respectively. 36,37 Benzene-1,2,4-tricarboxylic 1,2-anhydride 4-chloride (3) and benzene-1,2,4-tricarboxylic anhydride (4) and were employed to prepare isomers of C2 in an effort to elucidate if the substitution pattern of carboxylates on the aromatic ring influences the amyloidogenic propensity of individual conjugates and their interaction with full-length amylin. C3, with a 3,4 substitution Reaction of the peptidyl resin with benzene-1,2,4-tricarboxylic acid anhydride (4) yielded a single isomer as the major product (C4). ...
... [33][34][35] In addition, sulfonated molecules such as 3-amino-1propanesulfonic acid and 1,3-propanedisulfonic acid have been shown to be effective inhibitors of Aβ and serum amyloid A aggregation respectively. 36,37 Benzene-1,2,4-tricarboxylic 1,2-anhydride 4-chloride (3) and benzene-1,2,4-tricarboxylic anhydride (4) and were employed to prepare isomers of C2 in an effort to elucidate if the substitution pattern of carboxylates on the aromatic ring influences the amyloidogenic propensity of individual conjugates and their interaction with full-length amylin. C3, with a 3,4 substitution Reaction of the peptidyl resin with benzene-1,2,4-tricarboxylic acid anhydride (4) yielded a single isomer as the major product (C4). ...
Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37 residue peptide hormone that is stored and co-secreted with insulin. hIAPP plays a pivotal role in type 2 diabetes and is the major component of amyloid deposits found in the pancreas of patients afflicted with the disease. The self-assembly of hIAPP and the formation of amyloid is linked to the death of insulin producing -cells. Recent findings suggest soluble hIAPP oligomers are the cytotoxic species responsible for -cell loss whereas amyloid fibrils themselves may indeed be innocuous. Potential avenues of therapeutic intervention include the development of compounds that prevent hIAPP self-assembly as well as those that reduce or eliminate lag time and rapidly accelerate the formation of amyloid fibrils. Both of these approaches minimize temporal exposure to soluble cytotoxic hIAPP oligomers. Towards this end our laboratory has pursued an electrostatic repulsion approach to the development of potential inhibitors and modulators of hIAPP self-assembly. Peptide conjugates were constructed in which benzene carboxylic acids of varying charge were employed as electrostatic disrupting elements and appended to the N-terminal of the hIAPP22-29 (NFGAILSS) self-recognition sequence. The self-assembly kinetics of conjugates were characterized by turbidity measurements and the structure of aggregates probed by Raman and CD spectroscopy while the morphology was assessed using transmission electron microscopy. Several benzene carboxylic acid peptide conjugates failed to self-assemble and some were found to inhibit the aggregation of full-length amylin while others served to enhance the rate of amyloid formation and/or increase the yield of amyloid produced. Studies reveal that the geometric display of free carboxylates on the benzene ring of the conjugates plays an important role in the activity of conjugates. In addition a number of free benzene carboxylic acids were found to modulate amylin self-assembly on their own. The results of these investigations confirm the viability of the electrostatic repulsion approach to the modulation of amyloid formation and may aid the design and development of potential therapeutic agents.
... In a phase II/III clinical trial involving 180 patients, 2-year treatment with eprodisate (800-2400 mg/day based on creatinine clearance) led to reduced disease worsening and reduced risk and speed of creatinine decline compared with placebo, but no significant effect on proteinuria, or death [76]. A confirmatory second phase III trial is ongoing (NCT01215747) [77]. ...
Systemic amyloidosis is caused by misfolding and extracellular deposition of one of an ever-growing list of circulating proteins, resulting in vital organ dysfunction and eventually death. Despite different predisposing conditions, including plasma cell dyscrasias [immunoglobulin light chain (AL) amyloidosis], long-lasting inflammation [reactive (AA) amyloidosis] or mutations (hereditary amyloidoses), clinical manifestations are conspicuously overlapping and mimic more prevalent conditions, significantly complicating and often delaying the recognition of these rare, complex diseases. However, refined diagnostic and imaging approaches and the increasing role of biomarkers, which help in establishing the diagnosis, assessing the prognosis and evaluating the response to therapy, have considerably improved the management of these conditions. The pillar of anti-amyloid therapy remains the prompt reduction or elimination of the amyloidogenic precursor. This is accomplished by targeting the underlying condition, and recent improvements in the treatment of plasma cell disorders and chronic inflammatory conditions have positively reverberated onto the management of AL and AA amyloidosis, respectively. Moreover, recent, substantial improvements in the understanding of the molecular underpinnings of systemic amyloidosis have unveiled different key steps in the amyloidogenic cascade which can be valid therapeutic targets. These include stabilizers of the native conformation of the amyloidogenic precursor, inhibitors of fibrillogenesis, amyloid fibril disruptors and promoters of amyloid clearance. Innovative pharmacological strategies, including rational, structure-based drug design, gene knockdown and immunotherapy, but also repurposing of old, safe drugs with newly recognized anti-amyloid properties, are currently being pursued already in the clinical setting, holding the promise of dramatically improving the outcome of these dismal conditions in the near future.
