title: Brazilin Inhibits Prostatic Acidic Phosphatase Fibrillogenesis and Decreases its Cytotoxicity.
abstract: A 39-amino acid peptide fragment that is derived from prostatic acidic phosphatase (PAP), PAP248-286, is secreted in large amounts in human semen and forms amyloid fibrils. These fibrils can capture HIV virions and increase the attachment of virions to target cells; as such, they are called a "semen-derived enhancer of virus infection" (SEVI). Therefore, the inhibition of the formation of PAP248-286amyloid fibrils is of great significance. Herein, we demonstrate that brazilin effectively inhibits PAP248-286aggregation. The inhibitory effect increases with increasing brazilin concentration. Thioflavin T fluorescence assays and TEM observations confirmed that a few fibrils formed when brazilin was present with PAP248-286in an equimolar concentration. Circular dichroism spectroscopy indicated that brazilin inhibited the secondary structural transitions from α-helices and random coils into β-sheets. Cytotoxicity assays showed that brazilin significantly decreased the cytotoxicity of the fibrils at 0.01 mmol L-1. Isothermal titration calorimetry revealed that hydrophobic interactions were the main driving force for the binding of brazilin to the PAP248-286monomer (dissociation constant, 4.03 μmol L-1), and that the binding affinity of brazilin for the fibrils was at least three orders of magnitude lower than that for the monomer. These results indicate that brazilin holds great potential as a small-molecule agent against SEVIs.
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300354, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300354, P. R. China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Biology and Guangdong Provincial Key Laboratory of Marine Biotechnology, College of Science, Shantou University, Shantou, Guangdong, 515063, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300354, P. R. China.
authors.forename: Yan
authors.identifier: http://orcid.org/0000-0001-5256-9571
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000135:Acid Phosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D016716:PC12 Cells; D066329:Protein Aggregates / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000682:Amyloid; D001578:Benzopyrans; D066329:Protein Aggregates; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; C044362:brazilin
keywords: aggregation; brazilin; cytotoxicity; inhibitors; peptides