Mechanisms of amyloid proteins aggregation and their inhibition by antibodies, small molecule inhibitors, nano-particles and nano-bodies

Salahuddin, Parveen; Khan, Rizwan Hasan; Furkan, Mohammad; Uversky, Vladimir N.; Islam, Zeyaul; Fatima, Mahvish

doi:10.1016/j.ijbiomac.2021.07.056

Cited by 30 publications

(17 citation statements)

References 123 publications

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“…As ongoing therapies and clinical trials for cancer have been discussed in previous sections, here we will focus on interventions that could alleviate neurodegenerative diseases. The disparities between the pathophysiology of distinct proteinopathies led to exploring many different types of interventions for preventing protein aggregation (Arosio et al 2014 ; Hyun and Shin 2021 ; Lashuel 2021 ; Salahuddin et al 2021 ). Such interventions can be classified as antibodies, protein stabilizers, nanoparticles, sequestering monomers and small molecule inhibitors of aggregation.…”

Section: Clinical Trials On Proteolytic Systems To Prevent Protein Aggregationmentioning

confidence: 99%

“…Two further independent studies supported these findings, boosting the confidence in immunization studies (Janus et al 2000 ; Morgan et al 2000 ). A potential explanation for these beneficial effects is that antibodies promote the clearance of amyloid plaques through phagocytosis mediated by Fc receptor, which is a surface protein found in many different types of immune cells (Bard et al 2003 ; Salahuddin et al 2021 ). Unfortunately, these studies came to a halt when early clinical trials resulted in serious side effects, including a death due to meningoencephalitis (NCT00021723) (Neugroschl and Sano 2010 ).…”

Section: Clinical Trials On Proteolytic Systems To Prevent Protein Aggregationmentioning

confidence: 99%

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Protein clearance strategies for disease intervention

Hommen

Bilican

2021

J Neural Transm

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Protein homeostasis, or proteostasis, is essential for cell function and viability. Unwanted, damaged, misfolded and aggregated proteins are degraded by the ubiquitin–proteasome system (UPS) and the autophagy-lysosome pathway. Growing evidence indicates that alterations in these major proteolytic mechanisms lead to a demise in proteostasis, contributing to the onset and development of distinct diseases. Indeed, dysregulation of the UPS or autophagy is linked to several neurodegenerative, infectious and inflammatory disorders as well as cancer. Thus, modulation of protein clearance pathways is a promising approach for therapeutics. In this review, we discuss recent findings and open questions on how targeting proteolytic mechanisms could be applied for disease intervention.

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Section: Clinical Trials On Proteolytic Systems To Prevent Protein Aggregationmentioning

confidence: 99%

Section: Clinical Trials On Proteolytic Systems To Prevent Protein Aggregationmentioning

confidence: 99%

Protein clearance strategies for disease intervention

Hommen

Bilican

2021

J Neural Transm

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“…It has been shown that these compounds can have different origins (synthetic, natural) and chemical nature (phenols, peptide, antibodies, small molecules, etc . ). − Even though many trials are actually ongoing, especially on natural compounds, no drugs have entered into clinical use yet: this can be mainly due to the inability of targeting protein interfaces without regular secondary structures that could be assumed as templates to design inhibitors. , Recently, multivalent systems (as dendrimers) were investigated to gain access to different protein subregions . Indeed, different Aβ regions contribute to amyloid aggregation: the N-terminus, hydrophobic core, so-called hinge and turn regions, and C-terminus. , Experimental data indicated that the C-terminal region of Aβ can be addressed by the cyclohexanehexol scaffold: indeed, the scyllo-inositol compound interferes with the fibrillization process and competes with endogenous phosphatidylinositol for binding to the Aβ polypeptide, appearing as a promising therapeutic agent, currently in Phase II trials …”

Section: Introductionmentioning

confidence: 99%

Glucosyl Platinum(II) Complexes Inhibit Aggregation of the C-Terminal Region of the Aβ Peptide

et al. 2022

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Neurodegenerative diseases are often caused by uncontrolled amyloid aggregation. Hence, many drug discovery processes are oriented to evaluate new compounds that are able to modulate self-recognition mechanisms. Herein, two related glycoconjugate pentacoordinate Pt(II) complexes were analyzed in their capacity to affect the self-aggregation processes of two amyloidogenic fragments, Aβ21–40 and Aβ25–35, of the C-terminal region of the β-amyloid (Aβ) peptide, the major component of Alzheimerʼs disease (AD) neuronal plaques. The most water-soluble complex, 1Pt dep , is able to bind both fragments and to deeply influence the morphology of peptide aggregates. Thioflavin T (ThT) binding assays, electrospray ionization mass spectrometry (ESI-MS), and ultraviolet–visible (UV–vis) absorption spectroscopy indicated that 1Pt dep shows different kinetics and mechanisms of inhibition toward the two sequences and demonstrated that the peptide aggregation inhibition is associated with a direct coordinative bond of the compound metal center to the peptides. These data support the in vitro ability of pentacoordinate Pt(II) complexes to inhibit the formation of amyloid aggregates and pave the way for the application of this class of compounds as potential neurotherapeutics.

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“…Mature amyloid fibers form stepwise ( Figure 1 ); starting with individual monomers of αSyn lumping together to form nuclei/oligomers (primary nucleation), these oligomers can bind additional monomers resulting in long individual fibers (elongation). Additionally, the process can be catalyzed by secondary processes; the surface of already formed fibers can work as a catalyst for the formation of new nuclei (secondary nucleation) and long fibers can break into shorter fragments creating new growing ends (fragmentation) [ 12 , 13 ]. Next, individual fibers can associate together to form thicker (mature) fibers.…”

Section: Introductionmentioning

confidence: 99%

Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells

Lorentzon

Horváth

Kumar

et al. 2021

IJMS

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Exposure to heavy metals, including arsenic and cadmium, is associated with neurodegenerative disorders such as Parkinson’s disease. However, the mechanistic details of how these metals contribute to pathogenesis are not well understood. To search for underlying mechanisms involving α-synuclein, the protein that forms amyloids in Parkinson’s disease, we here assessed the effects of arsenic and cadmium on α-synuclein amyloid formation in vitro and in Saccharomyces cerevisiae (budding yeast) cells. Atomic force microscopy experiments with acetylated human α-synuclein demonstrated that amyloid fibers formed in the presence of the metals have a different fiber pitch compared to those formed without metals. Both metal ions become incorporated into the amyloid fibers, and cadmium also accelerated the nucleation step in the amyloid formation process, likely via binding to intermediate species. Fluorescence microscopy analyses of yeast cells expressing fluorescently tagged α-synuclein demonstrated that arsenic and cadmium affected the distribution of α-synuclein aggregates within the cells, reduced aggregate clearance, and aggravated α-synuclein toxicity. Taken together, our in vitro data demonstrate that interactions between these two metals and α-synuclein modulate the resulting amyloid fiber structures, which, in turn, might relate to the observed effects in the yeast cells. Whilst our study advances our understanding of how these metals affect α-synuclein biophysics, further in vitro characterization as well as human cell studies are desired to fully appreciate their role in the progression of Parkinson’s disease.

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Mechanisms of amyloid proteins aggregation and their inhibition by antibodies, small molecule inhibitors, nano-particles and nano-bodies

Cited by 30 publications

References 123 publications

Protein clearance strategies for disease intervention

Protein clearance strategies for disease intervention

Glucosyl Platinum(II) Complexes Inhibit Aggregation of the C-Terminal Region of the Aβ Peptide

Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells

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