ADS-J1 Inhibits Semen-Derived Amyloid Fibril Formation and Blocks Fibril-Mediated Enhancement of HIV-1 Infection

Xun, Tianrong; Li, Wenjuan; Chen, Jinquan; Yu, Fei; Xu, Wei; Wang, Qian; Yu, Ruizhe; Li, Xiaojuan; Zhou, Xuefeng; Lu, Lu; Jiang, Shibo; Li, Lin; Tan, Suiyi; Liu, Shuwen

doi:10.1128/aac.00385-15

Cited by 17 publications

(28 citation statements)

References 36 publications

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“…Therefore, therapeutic options capable to counteract the factors involved in the sexual transmission process are actively sought (12). In this study, we found that ADS-J1, apart from being an HIV-1 entry inhibitor, SEVI fibril inhibitor and blocker (3,13,31), was also an effective SEVI fibril disassembler. We found that ADS-J1 could effectively disrupt seminal amyloid fibrils, including SEVI fibrils and SEM1 fibrils as evidenced by loss of ThT fluorescence, disappearance of fibrils in TEM images, reduced particle size (Fig.1), impaired ability to enhance HIV-1 infection (Fig.2) and accumulated peptide monomer in remodeled products (Fig.…”

Section: Discussionmentioning

confidence: 76%

“…Both oral and topical pre-exposure prophylaxis (PrEP) are promising approaches to reduce HIV-1 sexual transmission (1). Although oral administration of tenofovir disoproxil fumarate/emtricitabine regimen has been a significant progress in HIV-1 prevention (2), the use of topical PrEP may be preferential over oral PrEP due to the rapid onset of protective drug levels at mucosal sites following administration and the potential reduction of systemic adverse effects (3). Development of topical microbicide is still urgent and challenging.…”

Section: Introductionmentioning

confidence: 99%

“…Due to its sulfonic groups, ADS-J1 binds to peptide PAP 248-286 and inhibits SEVI fibril formation. In addition, it coats on and shields the positive charges of mature SEVI fibrils, thus antagonizing fibril-mediated enhancement of HIV-1 infection (3). Unlike polyanions, which have failed in clinical trials, ADS-J1 does not accelerate SEVI fibril formation at low concentrations (15).…”

Section: Introductionmentioning

confidence: 99%

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ADS-J1 Disaggregates Semen-derived Amyloid Fibrils

Yang

Liu

et al. 2018

Preprint

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Semen-derived amyloid fibrils, composing SEVI (semen-derived enhancer of viral infection) fibrils and SEM1 fibrils, could remarkably enhance HIV-1 sexual transmission and thus, are potential targets for the development of an effective microbicide. Previously, we found that ADS-J1, apart from being an HIV-1 entry inhibitor, could also potently inhibit seminal amyloid fibrillization and block fibril-mediated enhancement of viral infection. However, the remodeling effects of ADS-J1 on mature seminal fibrils were unexplored. Herein, we investigated the capacity of ADS-J1 to disassemble seminal fibrils and the potential mode of action by applying several biophysical and biochemical measurements, combined with molecular dynamic (MD) simulations. We found that ADS-J1 effectively remodeled SEVI, SEM1 86-107 fibrils and endogenous seminal fibrils. Unlike epi-gallocatechin gallate (EGCG), a universal amyloid fibril breaker, ADS-J1 disaggregated SEVI fibrils into monomeric peptides, which was independent of oxidation reaction. MD simulations revealed that ADS-J1 displayed strong binding potency to the full-length PAP 248-286 via electrostatic interactions, hydrophobic interactions and hydrogen bonds.ADS-J1 might initially bind to the fibrillar surface and then occupy the amyloid core, which eventually lead to fibril disassembly. Furthermore, the binding of ADS-J1 with PAP 248-286 might induce conformational changes of PAP . Disassembled PAP 248-286 might not be favor to re-aggregate into fibrils. ADS-J1 also exerts abilities to remodel a panel of amyloid fibrils, including Aβ 1-42 , hIAPP 1-37 and EP2 fibrils.ADS-J1 displays promising potential to be a combination microbicide and an effective lead-product to treat amyloidogenic diseases.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ADS-J1 Disaggregates Semen-derived Amyloid Fibrils

Yang

Liu

et al. 2018

Preprint

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“…56 Binding of ADS-J1 to SEVI precursors obviously inhibited amyloidogenesis in a dose dependent manner. 77 A recent study demonstrated that brazilin, a natural compound that is isolated from Caesalpinia sappan, bound to SEVI precursors and inhibited amyloid formation at lower concentrations than EGCG. 78 In addition, nonhemolytic 11-residue peptides inhibited the formation of Ab(1-40) amyloid fibrils by interacting with the N-terminal part and the central hydrophobic cluster of Ab .…”

Section: Stabilization Of Sevi Precursors (Methods 7)mentioning

confidence: 99%

Semen‐derived amyloidogenic peptides—Key players of HIV infection

Lee

Ramamoorthy

2018

Protein Science

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Misfolding and amyloid aggregation of intrinsically disordered proteins (IDPs) are implicated in a variety of diseases. Studies have shown that membrane plays important roles on the formation of intermediate structures of IDPs that can initiate (and/or speed-up) amyloid aggregation to form fibers. The process of amyloid aggregation also disrupts membrane to cause cell death in amyloid diseases like Alzheimer's disease and type-2 diabetes. On the other hand, recent studies reported the membrane fusion properties of amyloid fibers. Remarkably, amyloid-fibril formation by short peptide fragments of highly abundant prostatic acidic-phosphatase (PAP) in human semen and are capable of boosting the rate of HIV infection up to 400,000-fold during sexual contact. Unlike the least toxic fully matured fibers of most amyloid proteins, the semen-derived enhancer of virus infection (SEVI) amyloid-fibrils of PAP peptide fragments are highly potent in rendering the maximum rate of HIV infection. This unusual property of amyloid fibers has witnessed increasing number of studies on the biophysical aspects of fiber formation and fiber-membrane interactions. NMR studies have reported a highly disordered partial helical structure in a membrane environment for the intrinsically disordered PAP peptide that promotes the fusion of the viral membrane with that of host cells. The purpose of this review article is to unify and integrate biophysical and immunological research reported in the previous studies on SEVI. Specifically, amyloid aggregation, dramatic HIV infection enhancing properties, membrane fusion properties, high resolution NMR structure, and approaches to eliminate the enhancement of HIV infection of SEVI peptides are discussed.

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“…Amyloid fibrils, which are a kind of highly ordered aggregates with rich β‐sheet structures, are related to a number of neurological diseases . Ramamoorthy et al.…”

Section: Introductionmentioning

confidence: 99%

Sulfonated Compounds Bind with Prostatic Acid Phosphatase (PAP_248–286) to Inhibit the Formation of Amyloid Fibrils

Zhang

Yang

et al. 2018

ChemistryOpen

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The peptide segment of prostatic acid phosphatase (PAP248–286) aggregates to form SEVI (semen‐derived enhancer of virus infection) amyloid fibrils. These are characteristic seminal amyloids that have the ability to promote the effect of HIV infection. In this paper, we explore the binding of sulfonated compounds with PAP248–286 through an in silico study. Three derivatives of suramin, NF110, NF279, and NF340, are selected. All of these sulfonated molecules bind to PAP248–286 and alter the conformation of the peptide, even though they have various structures, sizes, and configurations. The compounds bind with PAP248–286 through multiple interactions, such as hydrogen‐bonding interactions, hydrophobic interactions, π–π stacking interactions, and electrostatic interactions. However, NF110, which has an X‐shaped configuration, has the highest binding affinity of the three derivatives investigated. We also perform surface plasmon resonance and a Congo red assay to validate the results. The interactions between PAP248–286 and the sulfonated compounds are proposed to depend on the orientations of the sulfonate groups and the specific configurations of the compounds instead of the number of sulfonate groups. NF110 molecules occupy the exposed binding sites of PAP248–286, blocking interactions between the peptides. Therefore, these compounds are important in inhibiting the aggregation of PAP248–286. Herein, we provide useful information to develop new efficient microbicides to antagonize seminal amyloid fibrils and to block HIV transmission.

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ADS-J1 Inhibits Semen-Derived Amyloid Fibril Formation and Blocks Fibril-Mediated Enhancement of HIV-1 Infection

Cited by 17 publications

References 36 publications

ADS-J1 Disaggregates Semen-derived Amyloid Fibrils

ADS-J1 Disaggregates Semen-derived Amyloid Fibrils

Semen‐derived amyloidogenic peptides—Key players of HIV infection

Sulfonated Compounds Bind with Prostatic Acid Phosphatase (PAP_248–286) to Inhibit the Formation of Amyloid Fibrils

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ADS-J1 Inhibits Semen-Derived Amyloid Fibril Formation and Blocks Fibril-Mediated Enhancement of HIV-1 Infection

Cited by 17 publications

References 36 publications

ADS-J1 Disaggregates Semen-derived Amyloid Fibrils

ADS-J1 Disaggregates Semen-derived Amyloid Fibrils

Semen‐derived amyloidogenic peptides—Key players of HIV infection

Sulfonated Compounds Bind with Prostatic Acid Phosphatase (PAP248–286) to Inhibit the Formation of Amyloid Fibrils

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Sulfonated Compounds Bind with Prostatic Acid Phosphatase (PAP_248–286) to Inhibit the Formation of Amyloid Fibrils