Inhibition of Arenaviruses by Combinations of Orally Available Approved Drugs

Abstract

Neglected diseases caused by arenaviruses such as Lassa (LASV) and filoviruses like Ebola (EBOV) primarily afflict resource-limited countries, where antiviral drug development is often minimal. Previous studies have shown that many approved drugs developed for other clinical indications inhibit EBOV and LASV and that combinations of these drugs provide synergistic suppression of EBOV, often by blocking discrete steps in virus entry. We hypothesize that repurposing combinations of orally administered approved drugs provides effective suppression of arenaviruses. In this report, we demonstrate that arbidol, an approved influenza antiviral previously shown to inhibit EBOV, LASV, and many other viruses, inhibits murine leukemia (MLV) reporter viruses pseudotyped with the fusion glycoproteins (GP) of other arenaviruses [Junin (JUNV), lymphocytic choriomeningitis virus (LCMV), and Pichinde (PICV)]. Arbidol and other approved drugs including aripiprazole, amodiaquine, sertraline, and niclosamide also inhibit infection of cells by infectious PICV, and arbidol, sertraline and niclosamide inhibit infectious LASV. Combining arbidol with aripiprazole or sertraline results in synergistic suppression of LASV and JUNV GP-bearing pseudoviruses. This proof-of-concept study shows that arenavirus infection in vitro can be synergistically inhibited by combinations of approved drugs. This approach may lead to a proactive strategy with which to prepare for and control known and new arenavirus outbreaks.

Screening and Identification of Lujo Virus Inhibitors Using a Recombinant Reporter Virus Platform

“…Furthermore, given our knowledge of ribavirin treatment in other arenavirus infections, in which it is only partially effective and associated with significant side effects, investigations into uncovering effective and safe arenavirus therapeutic options are badly needed [ 7 ]. High-throughput screening assays utilizing recombinant reporter viruses as surrogates for the wild-type parental virus have previously been successful in identifying several anti-mammarenavirus compounds [ 15 , 16 , 46 , 47 ]. Here, using a novel recombinant reporter LUJV, we were able to identify six compounds with high efficacy against LUJV that warrant further evaluation.…”

Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses

“…While emergence of drug resistance is less certain for acute viral infections, which are usually eliminated by the acquired immune response ( 16 ), SARS-CoV-2 and influenza infections in immunocompromised hosts are notable for prolonged viral persistence at high viral loads with considerable ongoing viral mutagenesis ( 60 – 65 ). Thus, developing combination therapies for acute viral infections is justified, and efforts are under way for influenza virus ( 66 ), Ebola virus ( 47 , 48 , 67 , 68 ), arenaviruses ( 69 ), and SARS-CoV-2. For Ebola virus, computational modeling ( 48 ) has suggested that combinations would provide superior in vivo activity to their single agent components.…”

Antiviral Efficacy of Ribavirin and Favipiravir against Hantaan Virus

“…5 days post-treatment, cells were lysed with 1% Triton-100 to obtain the background values. Ribavirin is the compound demonstrating the highest relative safety with a therapeutic index of 4.9 × 10 5 :1, while favipiravir has a lower therapeutic index of To evaluate antagonistic or synergistic effects, we used the Bliss independence model, which states that two drugs have an independent effect, and their combination is calculated based on the probability of independent events [26][27][28]. As ribavirin and favipiravir have been demonstrated to block infection via distinct modes of action, they are considered to act independently [23].…”