Structure activity relationship of phenolic acid inhibitors of Î±-synuclein fibril formation and toxicity

Ardah, Mustafa T.; Paleologou, Katerina E.; Lv, Guohua; Khair, Salema B. Abul; Kazim, Abdulla S.; Minhas, Saeed Tariq; Al‐Tel, Taleb H.; Al-Hayani, Abdulmonem; Haque, M. Emdadul; Eliezer, David; El-Agnaf, Omar M. A.

doi:10.3389/fnagi.2014.00197

Cited by 106 publications

(116 citation statements)

References 84 publications

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“…Interestingly, however, the addition of gallic acid to monomeric peptides inhibited fibril formation (Fig. 3, E and F), consistent with prior reports of gallic acid as a fibrillation inhibitor (21)(22)(23)(24)(25).…”

Section: Resultssupporting

confidence: 80%

“…We identified from this screen the compound gallic acid, a phenol found in grape seed extract. Gallic acid has been shown to inhibit formation of ␣-synuclein, insulin, and amyloid-␤ amyloid fibrils (21)(22)(23)(24)(25). It is structurally related to the polyphenol epigallocatechin-3-gallate, a natural component found in green tea that was previously demonstrated to prevent formation of SEVI fibrils from PAPf39 monomers and to even degrade preformed fibrils (18,26,27).…”

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confidence: 99%

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Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection

LoRicco

Neidleman

et al. 2016

Journal of Biological Chemistry

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Recent in vitro studies have demonstrated that amyloid fibrils found in semen from healthy and HIV-infected men, as well as semen itself, can markedly enhance HIV infection rates. Semen fibrils are made up of multiple naturally occurring peptide fragments derived from semen. The best characterized of these fibrils are SEVI (semen-derived enhancer of viral infection), made up of residues 248 -286 of prostatic acidic phosphatase, and the SEM1 fibrils, made up of residues 86 -107 of semenogelin 1. A small molecule screen for antagonists of semen fibrils identified four compounds that lowered semen-mediated enhancement of HIV-1 infectivity. One of the four, gallic acid, was previously reported to antagonize other amyloids and to exert anti-inflammatory effects. To better understand the mechanism by which gallic acid modifies the properties of semen amyloids, we performed biophysical measurements (atomic force microscopy, electron microscopy, confocal microscopy, thioflavin T and Congo Red fluorescence assays, zeta potential measurements) and quantitative assays on the effects of gallic acid on semen-mediated enhancement of HIV infection and inflammation. Our results demonstrate that gallic acid binds to both SEVI and SEM1 fibrils and modifies their surface electrostatics to render them less cationic. In addition, gallic acid decreased semen-mediated enhancement of HIV infection but did not decrease the inflammatory response induced by semen. Together, these observations identify gallic acid as a non-polyanionic compound that inhibits semen-mediated enhancement of HIV infection and suggest the potential utility of incorporating gallic acid into a multicomponent microbicide targeting both the HIV virus and host components that promote viral infection.Amyloid fibrils are ordered protein aggregates associated with a large number of human diseases, many of which are neurodegenerative in nature, such as Alzheimer disease and Parkinson disease (1-3). They are characterized by their cross-␤ structure, with ␤ sheets running perpendicular to the fibril axis, and by their ability to bind to certain fluorescent dyes, such as thioflavin T (ThT), 4 whose fluorescence intensity increases considerably upon binding to amyloid fibrils.Amyloid fibrils are also found in semen from young, healthy men (4). Whether these fibrils serve a physiological function is not known, but they have been shown to markedly increase infection by a variety of sexually transmitted viruses, most notably HIV-1 (5-7). Under limiting dilution conditions, semen fibrils can increase HIV infection rates by up to 5 orders of magnitude (6). These fibrils are made up of naturally occurring peptide fragments in semen (6, 8 -10). The best characterized semen fibril is made up of a 39-residue fragment from human prostatic acid phosphatase (PAPf39) and has been termed SEVI (semen-derived enhancer of viral infection) (6). More recently, a second set of semen fibrils was identified from prostate-specific antigen-generated fragments of semenogelin (referred to collectivel...

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Section: Resultssupporting

confidence: 80%

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confidence: 99%

Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection

LoRicco

Neidleman

et al. 2016

Journal of Biological Chemistry

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“…The expression and purification was carried out as described elsewhere (Ardah et al, 2014). Briefly, the construct was inserted into BL21 E.coli bacteria by heat shock.…”

Section: Methodsmentioning

confidence: 99%

Ginsenoside Rb1 inhibits fibrillation and toxicity of alpha-synuclein and disaggregates preformed fibrils

Ardah

Paleologou

et al. 2015

Neurobiology of Disease

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Compelling evidence indicates that α-synuclein (α-syn) aggregation plays a central role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies. Identification of compounds that inhibit or reverse the aggregation process may thus represent a viable therapeutic strategy against PD and related disorders. Ginseng is a well-known medicinal plant that has been used in East Asia for more than two thousand years to treat several conditions. It is now understood that the pharmacological properties of ginseng can be attributed to its biologically active components, the ginsenosides, which in turn have been shown to have neuroprotective properties. We therefore sought to determine for the first time, the potential of the most frequently used and studied ginsenosides, namely Rg1, Rg3 and Rb1, as anti-amyloidogenic agents. The effect of Rg1, Rg3 and Rb1 on α-syn aggregation and toxicity was determined by an array of biophysical, biochemical and cell-culture-based techniques. Among the screened ginsenosides, only Rb1 was shown to be a potent inhibitor of α-syn fibrillation and toxicity. Additionally, Rb1 exhibited a strong ability to disaggregate preformed fibrils and to inhibit the seeded polymerization of α-syn. Interestingly, Rb1 was found to stabilize soluble non-toxic oligomers with no β-sheet content, that were susceptible to proteinase K digestion, and the binding of Rb1 to those oligomers may represent a potential mechanism of action. Thus, Rb1 could represent the starting point for designing new molecules that could be utilized as drugs for the treatment of PD and related disorders.

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“…; Ardah et al . , ; Wrasidlo et al . ), increasing the clearance of α‐syn via autophagy (Sarkar et al .…”

Section: Therapeutic Strategies In Synucleinopathiesmentioning

confidence: 99%

Antibodies against alpha‐synuclein: tools and therapies

Vaikath

Hmila

Gupta

et al. 2019

Journal of Neurochemistry

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Synucleinopathies including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterized by the abnormal accumulation and propagation of α‐synuclein (α‐syn) pathology in the central and peripheral nervous system as Lewy bodies or glial cytoplasmic inclusions. Several antibodies against α‐syn have been developed since it was first detected as the major component of Lewy bodies and glial cytoplasmic inclusions. Over the years, researchers have generated specific antibodies that alleviate the accumulation of intracellular aggregated α‐syn and associated pathology in cellular and preclinical models of synucleinopathies. So far, antibodies have been the first choice as tools for research and diagnosis and currently, a wide variety of antibody fragments have been developed as an alternative to full‐length antibodies for increasing its therapeutic usefulness. Recently, conformation specific antibody‐based approaches have been found to be promising as therapeutic strategies, both to block α‐syn aggregation and ameliorate the resultant cytotoxicity, and as diagnostic tools. In this review, we summarize different α‐syn specific antibodies and provide their usefulness in tackling synucleinopathies. This article is part of the Special Issue “Synuclein”.

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Structure activity relationship of phenolic acid inhibitors of Î±-synuclein fibril formation and toxicity

Cited by 106 publications

References 84 publications

Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection

Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection

Ginsenoside Rb1 inhibits fibrillation and toxicity of alpha-synuclein and disaggregates preformed fibrils

Antibodies against alpha‐synuclein: tools and therapies

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