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Inhibitory Effect of Naphthoquinone-Tryptophan Hybrid towards Aggregation of PAP f39 Semen Amyloid

1
School of Molecular Microbiology & Biotechnology, Tel Aviv University, Tel Aviv 69978, Israel
2
Department of Chemistry, Ilse Katz Institute (IKI) for Nanoscale Science and Technology, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
3
Sagol Interdisciplinary School of Neurosciences, Tel Aviv University, Tel Aviv 69978, Israel
*
Author to whom correspondence should be addressed.
These authors contributed equally to the work.
Academic Editor: Gal Bitan
Molecules 2018, 23(12), 3279; https://doi.org/10.3390/molecules23123279
Received: 14 November 2018 / Revised: 3 December 2018 / Accepted: 7 December 2018 / Published: 11 December 2018
(This article belongs to the Special Issue Amyloid Inhibitors and Modulators)
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. View Full-Text
Keywords: polypeptide aggregation; amyloid inhibition; NQTrp; PAP248–286 peptide; semen amyloids polypeptide aggregation; amyloid inhibition; NQTrp; PAP248–286 peptide; semen amyloids
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Viswanathan, G.K.; Mohapatra, S.; Paul, A.; Arad, E.; Jelinek, R.; Gazit, E.; Segal, D. Inhibitory Effect of Naphthoquinone-Tryptophan Hybrid towards Aggregation of PAP f39 Semen Amyloid. Molecules 2018, 23, 3279.

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