Tolcapone Potently Inhibits Seminal Amyloid Fibrils Formation and Blocks Entry of Ebola Pseudoviruses.

Mengjie Qiu,Jiayin Guo,Yurong Qiu,Lin Li,Shuwen Liu,Tao Qi,Suiyi Tan,Wei Xu,Jianxin Pang,Zhaofeng Li,Yuliu Chen

doi:10.3389/fmicb.2020.00504

Abstract

Ebola virus (EBOV), the causative pathogen of the deadly EBOV disease (EVD), can be transmitted via sexual transmission. Seminal amyloid fibrils have been found enhancers of EBOV infection. Currently, limited preventive vaccine or therapeutic is available to block EBOV infection through sexual intercourse. In this study, we repurpose tolcapone, a US Food and Drug Administration (FDA)-approved agent for Parkinson’s disease, as a potent inhibitor of seminal amyloid fibrils, among which semen-derived enhancer of viral infection (SEVI) is the best-characterized. Tolcapone binds to the amyloidogenic region of the SEVI precursor peptide (PAP248–286) and inhibits PAP248–286 aggregation by disrupting PAP248–286 oligomerization. In addition, tolcapone interacts with preformed SEVI fibrils and influences the activity of SEVI in promoting infection of pseudovirus (PsV) carrying the envelope glycoprotein (GP) of the EBOV Zaire or Sudan species (Zaire PsV and Sudan PsV, respectively). Tolcapone significantly antagonizes SEVI-mediated enhancement of both Zaire PsV and Sudan PsV binding to and subsequent internalization in HeLa cells. Of note, tolcapone is also effective in inhibiting the entry of both Zaire PsV and Sudan PsV. Tolcapone inhibits viral entry possibly through binding with critical residues in EBOV GP. Moreover, the combination of tolcapone with two small-molecule entry inhibitors, including bepridil and sertraline, exhibited synergistic anti-EBOV effects in semen. Collectively, as a bifunctional agent targeting the viral infection-enhancing amyloid and the virus itself during sexual intercourse, tolcapone can act as either a prophylactic topical agent to prevent the sexual transmission of EBOV or a therapeutic to treat EBOV infection.

Highlights

Ebola virus (EBOV) is the causative pathogen of the deadly EBOV disease (EVD). It belongs to the Filoviridae family and can be classified into six distinct species, including Zaire ebolavirus (ZEBOV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV), Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), and the newly identified Bombali ebolavirus (BOMV) (Van Kerkhove et al, 2015; Goldstein et al, 2018)
Tolcapone was firstly assessed for its effects on inhibiting the spontaneous amyloidogenesis of PAP248–286, the wellcharacterized seminal amyloidogenic peptide
The results demonstrate that tolcapone could effectively inhibit PAP248–286 aggregation

Summary

Introduction

Ebola virus (EBOV) is the causative pathogen of the deadly EBOV disease (EVD). It belongs to the Filoviridae family and can be classified into six distinct species, including Zaire ebolavirus (ZEBOV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV), Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), and the newly identified Bombali ebolavirus (BOMV) (Van Kerkhove et al, 2015; Goldstein et al, 2018). After the first recognized outbreak in 1976, numerous EBOV outbreaks have occurred over the years. It was only until the recent outbreak of EBOV in 2014–2016, which caused approximately 28,200 cases and 11,300 deaths, highlighted the danger and global impact of this pathogen. The epidemic has subsided, the increase in outbreak frequency, number of cases, and associated social and economic cost necessitates the need for effective vaccines and drugs to combat this pandemic threat (Dhama et al, 2018)

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