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

ABSTRACT: 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, ?-? 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.

SUBMITTER: Zhang T

PROVIDER: S-EPMC5997223 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Zhang Tingting T Yang Haikui H Yang Zichao Z Tan Suiyi S Jin Jiabin J Liu Shuwen S Zhang Jiajie J

ChemistryOpen 20180611 6

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 PAP2 ...[more]

PMID: 29928568

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Project description:The misfolding and aggregation of amyloid-? (A?) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer's disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of A?1-42 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against A?-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent A? peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic ?-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-A? and TS2-A? systems also interpret different inhibitory effects on A? aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of A? inhibitors to prevent and disaggregate amyloid formation.

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

Publications

Sulfonated Compounds Bind with Prostatic Acid Phosphatase (PAP<sub>248-286</sub>) to Inhibit the Formation of Amyloid Fibrils.

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