Identification of a clinical compound losmapimod that blocks Lassa virus entry

Zhang, Xiaoyu; Yan, Feihu; Tang, Ke; Chen, Qing; Guo, Jiamei; Zhu, Wenjun; He, Shihua; Banadyga, Logan; Qiu, Xiangguo; Guo, Ying

doi:10.1016/j.antiviral.2019.03.014

Cited by 23 publications

(21 citation statements)

References 38 publications

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“…In addition, we observed a reduction in viral E1 protein expression, suggesting that p38 might serve as a therapeutical target to control MAYV infection. Zhang and collaborators showed that Losmapimod is able to inhibit Lassa virus entry, although through a mechanism not involving p38 inhibition [ 58 ]. In another study, Losmapimod was shown to disrupt SARS-CoV-2 replication in a model of primary alveolar epithelial cells, suggesting that p38 is a potential target for COVID-19 treatment [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Sugasti-Salazar

Llamas-González

Campos

et al. 2021

Viruses

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Mayaro virus (MAYV) hijacks the host’s cell machinery to effectively replicate. The mitogen-activated protein kinases (MAPKs) p38, JNK, and ERK1/2 have emerged as crucial cellular factors implicated in different stages of the viral cycle. However, whether MAYV uses these MAPKs to competently replicate has not yet been determined. The aim of this study was to evaluate the impact of MAPK inhibition on MAYV replication using primary human dermal fibroblasts (HDFs) and HeLa cells. Viral yields in supernatants from MAYV-infected cells treated or untreated with inhibitors SB203580, SP600125, U0126, or Losmapimod were quantified using plaque assay. Additionally, viral protein expression was analyzed using immunoblot and immunofluorescence. Knockdown of p38⍺/p38β isoforms was performed in HDFs using the PROTACs molecule NR-7h. Our data demonstrated that HDFs are highly susceptible to MAYV infection. SB203580, a p38 inhibitor, reduced MAYV replication in a dose-dependent manner in both HDFs and HeLa cells. Additionally, SB203580 significantly decreased viral E1 protein expression. Similarly, knockdown or inhibition of p38⍺/p38β isoforms with NR-7h or Losmapimod, respectively, affected MAYV replication in a dose-dependent manner. Collectively, these findings suggest that p38 could play an important role in MAYV replication and could serve as a therapeutic target to control MAYV infection.

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Section: Discussionmentioning

confidence: 99%

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Sugasti-Salazar

Llamas-González

Campos

et al. 2021

Viruses

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“…Drug screens have identified small molecules with activity against LASV and other arenaviruses. Most are investigational drugs and include clotrimazole derivatives ( 7 ), ST-193 ( 8 , 9 ), F3406 ( 10 ), LHF-535 ( 11 ), kinase inhibitors ( 12 , 13 ), losmapimod ( 14 ), and inhibitors of purine and pyrimidine biosynthesis ( 15 – 17 ). The polymerase inhibitors remdesivir and favipiravir have shown some activity against arenaviruses in cell cultures ( 18 ) and in vivo ( 19 ), respectively.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Arenaviruses by Combinations of Orally Available Approved Drugs

Herring

Oda

Wagoner

et al. 2021

Antimicrob Agents Chemother

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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.

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“…In addition, we observed a reduction in viral E1 protein expression, suggesting that p38 might be to a therapeutical target to control MAYV infection. Zhang and collaborators showed that Losmapimod is able to inhibit Lassa virus entry, although through a mechanism not involving p38 inhibition [57]. In another study, Losmapimod was shown to disrupt SARS-CoV-2 replication in a model of primary alveolar epithelial cells, suggesting that p38 is a potential target for COVID-19 treatment [58].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Sugasti¹,

Llamas-González²,

Campos³

et al. 2021

Preprint

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Mayaro virus (MAYV) hijacks the host´s cell machinery to effectively replicate. The mitogen-activated protein kinases (MAPKs) p38, JNK and ERK1/2 have emerged as crucial cellular factors implicated in different stages of the viral cycle. However, whether MAYV uses these MAPKs to competently replicate has not yet been determined. The aim of this study was to evaluate the impact of MAPKs inhibition on MAYV replication using primary human dermal fibroblasts (HDFs) and HeLa cells. Viral yields in supernatants from MAYV-infected cells treated or untreated with inhibitors SB203580, SP600125, U0126 or Losmapimod were quantified using plaque assay. Also, viral protein expression was analyzed using immunoblot and immunofluorescence. Knockdown of p38⍺/p38β isoforms was performed in HDFs using the PROTACs molecule NR-7h. Our data demonstrated that HDFs are highly susceptible to MAYV infection. SB203580, a p38 inhibitor, reduced MAYV replication in a dose-dependent manner in both HDFs and HeLa cells. Additionally, SB203580 significantly decreased viral E1 protein expression. Similarly, knockdown or inhibition of p38⍺/p38β isoforms with NR-7h or Losmapimod, respectively, affected MAYV replication in a dose-dependent manner. Collectively, these findings suggest that p38 could play an important role in MAYV replication and could serve as a therapeutic target to control MAYV infection.

show abstract

Identification of a clinical compound losmapimod that blocks Lassa virus entry

Cited by 23 publications

References 38 publications

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Inhibition of Arenaviruses by Combinations of Orally Available Approved Drugs

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

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