Inhibitory Effect of Naphthoquinone-Tryptophan Hybrid towards Aggregation of PAP f39 Semen Amyloid
| Autor: | Ehud Gazit, Ashim Paul, Raz Jelinek, Elad Arad, Guru KrishnaKumar Viswanathan, Daniel L. Segal, Satabdee Mohapatra |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Amyloid Protein Conformation Acid Phosphatase Pharmaceutical Science Peptide 010402 general chemistry 01 natural sciences Analytical Chemistry lcsh:QD241-441 03 medical and health sciences chemistry.chemical_compound lcsh:Organic chemistry polypeptide aggregation semen amyloids Drug Discovery NQTrp Physical and Theoretical Chemistry Coloring Agents chemistry.chemical_classification Binding Sites Dose-Response Relationship Drug Communication Organic Chemistry Tryptophan Isothermal titration calorimetry Congo Red PAP248–286 peptide Small molecule In vitro Naphthoquinone Peptide Fragments 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology chemistry Prostatic acid phosphatase Biochemistry Chemistry (miscellaneous) Molecular Medicine Thermodynamics amyloid inhibition Naphthoquinones |
| Zdroj: | Molecules Molecules, Vol 23, Iss 12, p 3279 (2018) |
| ISSN: | 1420-3049 |
| Popis: | PAP248⁻286, a 39 amino acid peptide fragment, derived from the prostatic acid phosphatase secreted in human semen, forms amyloid fibrils and facilitates the attachment of retroviruses to host cells that results in the enhancement of viral infection. Therefore, the inhibition of amyloid formation by PAP248⁻286 (termed PAP f39) may likely reduce HIV transmission in AIDS. In this study, we show that the naphthoquinone tryptophan (NQTrp) hybrid molecule significantly inhibited PAP f39 aggregation in vitro in a dose-dependent manner as observed from the ThT assay, ANS assay, and transmission electron microscopy imaging. We found that even at a sub-molar concentration of 20:1 [PAP f39:NQTrp], NQTrp could reduce >50% amyloid formation. NQTrp inhibition of PAP f39 aggregation resulted in non-toxic intermediate species as determined by the vesicle leakage assay. Isothermal titration calorimetry and molecular docking revealed that the binding of NQTrp and PAP f39 is spontaneous, and NQTrp predominantly interacts with the polar and charged residues of the peptide by forming hydrogen bonds and hydrophobic contacts with a strong binding energy. Collectively, these findings indicate that NQTrp holds significant potential as a small molecule inhibitor of semen amyloids. |
| Databáze: | OpenAIRE |
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