Sertraline Is an Effective SARS-CoV-2 Entry Inhibitor Targeting the Spike Protein.

The global spread of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the continuously emerging new variants underscore an urgent need for effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). Here, we screened several FDA-approved amphiphilic drugs and determined that sertraline (SRT) exhibits potent antiviral activity against infection of SARS-CoV-2 pseudovirus (PsV) and authentic virus in vitro. It effectively inhibits SARS-CoV-2 spike (S)-mediated cell-cell fusion. SRT targets the early stage of viral entry. It can bind to the S1 subunit of the S protein, especially the receptor binding domain (RBD), thus blocking S-hACE2 interaction and interfering with the proteolysis process of S protein. SRT is also effective against infection with SARS-CoV-2 PsV variants, including the newly emerging Omicron. The combination of SRT and other antivirals exhibits a strong synergistic effect against infection of SARS-CoV-2 PsV. The antiviral activity of SRT is independent of serotonin transporter expression. Moreover, SRT effectively inhibits infection of SARS-CoV-2 PsV and alleviates the inflammation process and lung pathological alterations in transduced mice in vivo. Therefore, SRT shows promise as a treatment option for COVID-19. IMPORTANCE The study shows SRT is an effective entry inhibitor against infection of SARS-CoV-2, which is currently prevalent globally. SRT targets the S protein of SARS-CoV-2 and is effective against a panel of SARS-CoV-2 variants. It also could be used in combination to prevent SARS-CoV-2 infection. More importantly, with long history of clinical use and proven safety, SRT might be particularly suitable to treat infection of SARS-CoV-2 in the central nervous system and optimized for treatment in older people, pregnant women, and COVID-19 patients with heart complications, which are associated with severity and mortality of COVID-19.

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

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.