scholarly journals CP100356 Hydrochloride, a P-Glycoprotein Inhibitor, Inhibits Lassa Virus Entry: Implication of a Candidate Pan-Mammarenavirus Entry Inhibitor

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1763
Author(s):  
Toru Takenaga ◽  
Zihan Zhang ◽  
Yukiko Muramoto ◽  
Sarah Katharina Fehling ◽  
Ai Hirabayashi ◽  
...  
Keyword(s):  
Virus Entry ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Entry Inhibitor ◽  
Lassa Virus ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Vesicular Stomatitis ◽  
Approved Drugs

Lassa virus (LASV)—a member of the family Arenaviridae—causes Lassa fever in humans and is endemic in West Africa. Currently, no approved drugs are available. We screened 2480 small compounds for their potential antiviral activity using pseudotyped vesicular stomatitis virus harboring the LASV glycoprotein (VSV-LASVGP) and a related prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV). Follow-up studies confirmed that CP100356 hydrochloride (CP100356), a specific P-glycoprotein (P-gp) inhibitor, suppressed VSV-LASVGP, LCMV, and LASV infection with half maximal inhibitory concentrations of 0.52, 0.54, and 0.062 μM, respectively, without significant cytotoxicity. Although CP100356 did not block receptor binding at the cell surface, it inhibited low-pH-dependent membrane fusion mediated by arenavirus glycoproteins. P-gp downregulation did not cause a significant reduction in either VSV-LASVGP or LCMV infection, suggesting that P-gp itself is unlikely to be involved in arenavirus entry. Finally, our data also indicate that CP100356 inhibits the infection by other mammarenaviruses. Thus, our findings suggest that CP100356 can be considered as an effective virus entry inhibitor for LASV and other highly pathogenic mammarenaviruses.

scholarly journals Screening of Botanical Drugs against Lassa Virus Entry

2021 ◽  
Author(s):  
Yang Liu ◽  
Jiao Guo ◽  
Junyuan Cao ◽  
Guangshun Zhang ◽  
Xiaoying Jia ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
High Throughput Screening ◽  
Transmembrane Domain ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Mechanistic Study ◽  
Lassa Virus ◽  
Potential Candidate ◽  
Botanical Drug ◽  
Approved Drugs

Lassa virus (LASV) belongs to the Old World Mammarenavirus genus (family Arenaviridae). At present, there are no approved drugs or vaccines specific for LASV. In this study, high-throughput screening of a botanical drug library was performed against LASV entry using a pseudotype virus bearing the LASV envelope glycoprotein complex (GPC). Two hit compounds, bergamottin and casticin, were identified as micromolar range inhibitors of LASV entry. A mechanistic study revealed that casticin inhibited LASV entry by blocking low pH-induced membrane fusion. Analysis of adaptive mutants demonstrated that the F446L mutation, located in the transmembrane domain of GP2, conferred resistance to casticin. Furthermore, casticin antiviral activity extends to the New World (NW) pathogenic mammarenaviruses, and mutation of the conserved F446 also conferred resistance to casticin in these viruses. Unlike casticin, bergamottin showed little effect on LASV GPC-mediated membrane fusion, instead inhibiting LASV entry by blocking endocytic trafficking. Notably, both compounds showed inhibitory effects on authentic lymphocytic choriomeningitis virus. Our study shows that both casticin and bergamottin are candidates for LASV therapy and that the conserved F446 in LASV GPC is important in drug resistance in mammarenaviruses. IMPORTANCE: Currently, there is no approved therapy to treat Lassa fever (LASF). Our goal was to identify potential candidate molecules for LASF therapy. Herein, we screened a botanical drug library and identified two compounds, casticin and bergamottin, that inhibited LASV entry via different mechanisms.

scholarly journals A recombinant vesicular stomatitis-based Lassa fever vaccine elicits rapid and long-term protection from lethal Lassa virus infection in guinea pigs

npj Vaccines ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Derek R. Stein ◽  
Bryce M. Warner ◽  
Geoff Soule ◽  
Kevin Tierney ◽  
Kathy L. Frost ◽  
...  
Keyword(s):  
Virus Infection ◽  
Guinea Pigs ◽  
Lassa Fever ◽  
Lassa Virus ◽  
Vesicular Stomatitis

scholarly journals Inhibition of Arenaviruses by Combinations of Orally Available Approved Drugs

2021 ◽  
Author(s):  
Shawn Herring ◽  
Jessica M. Oda ◽  
Jessica Wagoner ◽  
Delaney Kirchmeier ◽  
Aidan O’Connor ◽  
...  
Keyword(s):  
Virus Entry ◽  
Antiviral Drug ◽  
Lymphocytic Choriomeningitis ◽  
Neglected Diseases ◽  
Proof Of Concept ◽  
Effective Suppression ◽  
Resource Limited ◽  
Approved Drugs ◽  
And Control

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.

scholarly journals Public health response to two imported, epidemiologically related cases of Lassa fever in the Netherlands (ex Sierra Leone), November 2019

2020 ◽  
Vol 25 (15) ◽  
Author(s):  
Femke Overbosch ◽  
Mark de Boer ◽  
Karin Ellen Veldkamp ◽  
Pauline Ellerbroek ◽  
Chantal P Bleeker-Rovers ◽  
...  
Keyword(s):  
Public Health ◽  
The Netherlands ◽  
Sierra Leone ◽  
Healthcare Facility ◽  
Lassa Fever ◽  
Low Risk ◽  
Lassa Virus ◽  
Public Health Response ◽  
Health Response

On 20 November 2019, Lassa fever was diagnosed in a physician repatriated from Sierra Leone to the Netherlands. A second physician with suspected Lassa fever, repatriated a few days later from the same healthcare facility, was confirmed infected with Lassa virus on 21 November. Comprehensive contact monitoring involving high- and low-risk contacts proved to be feasible and follow-up of the contacts did not reveal any case of secondary transmission in the Netherlands.

scholarly journals MEMANTINE, AS A P-GLYCOPROTEIN EXPRESSION MODULATOR, ENHANCES LEVETIRACETAM THERAPEUTIC RESPONSE IN EPILEPTIC PATIENTS

2020 ◽  
pp. 104-108
Author(s):  
SAHAR AHMED HARBY ◽  
RASHA A NASSRA ◽  
JAIDAA F MEKKY ◽  
SAMIA M ALI ◽  
CHERINE A ISMAIL
Keyword(s):  
Therapeutic Response ◽  
Seizure Control ◽  
Multidrug Transporter ◽  
Potential Therapeutic Target ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Epileptic Patients ◽  
Patients With Epilepsy ◽  
Transporter Expression

Objective: The principal aim of the present study was to assess the importance of multidrug transporter; P-glycoprotein (P-gp) as a potential therapeutic target in patients with epilepsy. Can P-gp transporter expression modulation by memantine add to the standard antiepileptic drugs (AEDs) response? Methods: A cohort of 56 epilepsy patients was included in a 4 monthly visits prospective study. Patients were on levetiracetam (LEV) 1000 mg/ day alone or combined with other AEDs. They were randomly assigned into two groups; LEV only group including LEV-treated patients and LEV + memantine group including patients on LEV with add-on oral memantine 10 mg/day until the end of the study. During monthly follow-up visits, therapeutic responses were evaluated for each patient by recording the monthly seizures frequency. Blood samples were drawn from every patient twice (on the first and last visits) for assessment of P-gp mRNA expression level. Results: Fifty patients completed the study. At the end of 4th month, LEV only group showed a non-significant decrease in P-gp expression and seizure frequency compared to the 1st month, whereas, in LEV + memantine group, P-gp expression was significantly reduced and associated with significant seizure control. Conclusion: Memantine by hindering P-gp overexpression was apt to enhance LEV efficacy and exhibit a better seizure control.

scholarly journals The Janus Kinase Inhibitor Ruxolitinib Prevents Terminal Shock in a Mouse Model of Arenavirus Hemorrhagic Fever

2021 ◽  
Vol 9 (3) ◽  
pp. 564
Author(s):  
Mehmet Sahin ◽  
Melissa M. Remy ◽  
Doron Merkler ◽  
Daniel D. Pinschewer
Keyword(s):  
Kinase Inhibitor ◽  
Antibody Therapy ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Janus Kinase ◽  
Lassa Virus ◽  
Jak Inhibitor ◽  
Medical Needs ◽  
Ifn Γ

Arenaviruses such as Lassa virus cause arenavirus hemorrhagic fever (AVHF), but protective vaccines and effective antiviral therapy remain unmet medical needs. Our prior work has revealed that inducible nitric oxide synthase (iNOS) induction by IFN-γ represents a key pathway to microvascular leak and terminal shock in AVHF. Here we hypothesized that Ruxolitinib, an FDA-approved JAK inhibitor known to prevent IFN-γ signaling, could be repurposed for host-directed therapy in AVHF. We tested the efficacy of Ruxolitinib in MHC-humanized (HHD) mice, which develop Lassa fever-like disease upon infection with the monkey-pathogenic lymphocytic choriomeningitis virus strain WE. Anti-TNF antibody therapy was tested as an alternative strategy owing to its expected effect on macrophage activation. Ruxolitinib but not anti-TNF antibody prevented hypothermia and terminal disease as well as pleural effusions and skin edema, which served as readouts of microvascular leak. As expected, neither treatment influenced viral loads. Intriguingly, however, and despite its potent disease-modifying activity, Ruxolitinib did not measurably interfere with iNOS expression or systemic NO metabolite levels. These findings suggest that the FDA-approved JAK-inhibitor Ruxolitinib has potential in the treatment of AVHF. Moreover, our observations indicate that besides IFN-γ-induced iNOS additional druggable pathways contribute essentially to AVHF and are amenable to host-directed therapy.

scholarly journals E3 Ligase ITCH Interacts with the Z Matrix Protein of Lassa and Mopeia Viruses and Is Required for the Release of Infectious Particles

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 49 ◽  
Author(s):  
Nicolas Baillet ◽  
Sophie Krieger ◽  
Xavier Carnec ◽  
Mathieu Mateo ◽  
Alexandra Journeaux ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Matrix Protein ◽  
Virus Assembly ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Lassa Virus ◽  
Yeast Two Hybrid ◽  
Ubiquitin Ligase Activity ◽  
Two Hybrid

Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related, rodent-born mammarenaviruses. LASV is the causative agent of Lassa fever, a deadly hemorrhagic fever endemic in West Africa, whereas MOPV is non-pathogenic in humans. The Z matrix protein of arenaviruses is essential to virus assembly and budding by recruiting host factors, a mechanism that remains partially defined. To better characterize the interactions involved, a yeast two-hybrid screen was conducted using the Z proteins from LASV and MOPV as a bait. The cellular proteins ITCH and WWP1, two members of the Nedd4 family of HECT E3 ubiquitin ligases, were found to bind the Z proteins of LASV, MOPV and other arenaviruses. The PPxY late-domain motif of the Z proteins is required for the interaction with ITCH, although the E3 ubiquitin-ligase activity of ITCH is not involved in Z ubiquitination. The silencing of ITCH was shown to affect the replication of the old-world mammarenaviruses LASV, MOPV, Lymphocytic choriomeningitis virus (LCMV) and to a lesser extent Lujo virus (LUJV). More precisely, ITCH was involved in the egress of virus-like particles and the release of infectious progeny viruses. Thus, ITCH constitutes a novel interactor of LASV and MOPV Z proteins that is involved in virus assembly and release.

scholarly journals Virus–Host Interactions Involved in Lassa Virus Entry and Genome Replication

Pathogens ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 17 ◽  
Author(s):  
María Loureiro ◽  
Alejandra D’Antuono ◽  
Nora López
Keyword(s):  
Rational Design ◽  
Virus Entry ◽  
Lassa Fever ◽  
Hemorrhagic Disease ◽  
Lassa Virus ◽  
Genome Replication ◽  
Host Proteins ◽  
Mortality And Morbidity ◽  
Host Interactions ◽  
Cellular Factors

Lassa virus (LASV) is the causative agent of Lassa fever, a human hemorrhagic disease associated with high mortality and morbidity rates, particularly prevalent in West Africa. Over the past few years, a significant amount of novel information has been provided on cellular factors that are determinant elements playing a role in arenavirus multiplication. In this review, we focus on host proteins that intersect with the initial steps of the LASV replication cycle: virus entry and genome replication. A better understanding of relevant virus–host interactions essential for sustaining these critical steps may help to identify possible targets for the rational design of novel therapeutic approaches against LASV and other arenaviruses that cause severe human disease.

scholarly journals A Live Attenuated Vaccine for Lassa Fever Made by Reassortment of Lassa and Mopeia Viruses

2005 ◽  
Vol 79 (22) ◽  
pp. 13934-13942 ◽  
Author(s):  
Igor S. Lukashevich ◽  
Jean Patterson ◽  
Ricardo Carrion ◽  
Dmitry Moshkoff ◽  
Anysha Ticer ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Rhesus Macaques ◽  
Detailed Examination ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Cell Mediated Immunity ◽  
Lassa Virus ◽  
Live Attenuated Vaccine ◽  
Attenuated Vaccine ◽  
Primary Virus

ABSTRACT Lassa virus (LASV) and Mopeia virus (MOPV) are closely related Old World arenaviruses that can exchange genomic segments (reassort) during coinfection. Clone ML29, selected from a library of MOPV/LASV (MOP/LAS) reassortants, encodes the major antigens (nucleocapsid and glycoprotein) of LASV and the RNA polymerase and zinc-binding protein of MOPV. Replication of ML29 was attenuated in guinea pigs and nonhuman primates. In murine adoptive-transfer experiments, as little as 150 PFU of ML29 induced protective cell-mediated immunity. All strain 13 guinea pigs vaccinated with clone ML29 survived at least 70 days after LASV challenge without either disease signs or histological lesions. Rhesus macaques inoculated with clone ML29 developed primary virus-specific T cells capable of secreting gamma interferon in response to homologous MOP/LAS and heterologous MOPV and lymphocytic choriomeningitis virus. Detailed examination of two rhesus macaques infected with this MOPV/LAS reassortant revealed no histological lesions or disease signs. Thus, ML29 is a promising attenuated vaccine candidate for Lassa fever.

scholarly journals Early Blood Profiles of Virus Infection in a Monkey Model for Lassa Fever

2007 ◽  
Vol 81 (15) ◽  
pp. 7960-7973 ◽  
Author(s):  
Mahmoud M. Djavani ◽  
Oswald R. Crasta ◽  
Juan Carlos Zapata ◽  
Zhangjun Fei ◽  
Otto Folkerts ◽  
...  
Keyword(s):  
Virus Infection ◽  
Rhesus Macaques ◽  
Lethal Dose ◽  
Disease Onset ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Lassa Virus ◽  
Monkey Model ◽  
Lcmv Infection

ABSTRACT Acute arenavirus disease in primates, like Lassa hemorrhagic fever in humans, begins with flu-like symptoms and leads to death approximately 2 weeks after infection. Our goal was to identify molecular changes in blood that are related to disease progression. Rhesus macaques (Macaca mulatta) infected intravenously with a lethal dose of lymphocytic choriomeningitis virus (LCMV) provide a model for Lassa virus infection of humans. Blood samples taken before and during the course of infection were used to monitor gene expression changes that paralleled disease onset. Changes in blood showed major disruptions in eicosanoid, immune response, and hormone response pathways. Approximately 12% of host genes alter their expression after LCMV infection, and a subset of these genes can discriminate between virulent and nonvirulent LCMV infection. Major transcription changes have been given preliminary confirmation by quantitative PCR and protein studies and will be valuable candidates for future validation as biomarkers for arenavirus disease.

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