Antiviral Ranpirnase TMR-001 Inhibits Rabies Virus Release and Cell-to-Cell Infection In Vitro

Smith, T.; Jackson, Felix R.; Morgan, Clint N.; Carson, William C.; Martin, Brock E.; Gallardo-Romero, Nadia; Ellison, James A.; Greenberg, L.; Hodge, Thomas; Squiquera, Luis; Sulley, Jamie; Olson, Victoria A.; Hutson, Christina L.

doi:10.3390/v12020177

Cited by 12 publications

(10 citation statements)

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“… 2019 ), and inhibition of RABV release (Smith et al . 2020 ). In addition, ribavirin, a broad-spectrum guanosine nucleoside analog, inhibits the virus infection by inhibiting mRNA expression (Kihira et al .…”

Section: Discussionmentioning

confidence: 99%

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Artesunate and Dihydroartemisinin Inhibit Rabies Virus Replication

et al. 2021

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Rabies is caused by infection of rabies virus (RABV) and remains a serious threat to the global public health. Except for the requirement for cold chain and high cost of human rabies immune globulin, no small molecule drugs are currently available for clinical treatment of rabies. So, it is of great importance to identify novel compounds that can effectively inhibit RABV infection. Artesunate (ART) and dihydroartemisinin (DHA), two derivatives of artemisinin, are widely used for treatment of malaria in adults and children, showing high safety. In this study, we found that both ART and DHA were able to inhibit RABV replication in host cells at a low concentration (0.1 μmol/L). The antiviral effects of ART and DHA were independent of viral strains and cell lines. Pre-treatment with ART or DHA for 2 h in vitro did not affect the viral replication in host cells, implying that ART and DHA neither reduced the viability of RABV directly nor inhibited the binding and entrance of the virus to host cells. Further studies revealed that ART and DHA inhibited RABV genomic RNA synthesis and viral gene transcription. Treatment with ART or DHA (5 mg/kg) by intramuscular injection improved, to some extent, the survival rate of RABV-challenged mice. Combination treatment with derivatives of artemisinin and mannitol significantly improved the survival rate of RABV-challenged mice. The results suggest that ART and DHA have a great potential to be explored as new anti-rabies agents for treatment of rabies.

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Section: Discussionmentioning

confidence: 99%

“…TMR-001, a proprietary bulk drug substance solution of ranpirnase, can inhibit RABV release and cell-to-cell infection in vitro (Smith et al . 2020 ). Pyrimethamine inhibits RABV replication in vitro through the inhibition of adenosine synthesis (Rogee et al .…”

Section: Introductionmentioning

confidence: 99%

Artesunate and Dihydroartemisinin Inhibit Rabies Virus Replication

et al. 2021

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“…Interestingly, the mechanism mediated by ATF3 is described as cell-type independent since the altered genes and the negative regulation of the JAK-STAT signaling pathway in ovarian cancer cell lines [ 96 ] are also found equally changed in different MM cell lines, derived from pleural tumors [ 68 ]. ONC also presents a very interesting antiviral activity [ 97 , 98 , 99 , 100 ], beyond RNA degradation, that is again mediated by ATF3 [ 96 ].…”

Section: Antitumor Rnases Exert Pleiotropic Effects On Cancer Cellmentioning

confidence: 99%

Strengths and Challenges of Secretory Ribonucleases as AntiTumor Agents

et al. 2021

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Approaches to develop effective drugs to kill cancer cells are mainly focused either on the improvement of the currently used chemotherapeutics or on the development of targeted therapies aimed at the selective destruction of cancer cells by steering specific molecules and/or enhancing the immune response. The former strategy is limited by its genotoxicity and severe side effects, while the second one is not always effective due to tumor cell heterogeneity and variability of targets in cancer cells. Between these two strategies, several approaches target different types of RNA in tumor cells. RNA degradation alters gene expression at different levels inducing cell death. However, unlike DNA targeting, it is a pleotropic but a non-genotoxic process. Among the ways to destroy RNA, we find the use of ribonucleases with antitumor properties. In the last few years, there has been a significant progress in the understanding of the mechanism by which these enzymes kill cancer cells and in the development of more effective variants. All the approaches seek to maintain the requirements of the ribonucleases to be specifically cytotoxic for tumor cells. These requirements start with the competence of the enzymes to interact with the cell membrane, a process that is critical for their internalization and selectivity for tumor cells and continue with the downstream effects mainly relying on changes in the RNA molecular profile, which are not only due to the ribonucleolytic activity of these enzymes. Although the great improvements achieved in the antitumor activity by designing new ribonuclease variants, some drawbacks still need to be addressed. In the present review, we will focus on the known mechanisms used by ribonucleases to kill cancer cells and on recent strategies to solve the shortcomings that they show as antitumor agents, mainly their pharmacokinetics.

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“…À ce jour, plusieurs molécules antivirales ont été testées contre la rage, et malgré une action antivirale efficace in vitro, les tests in vivo chez la souris ou le hamster syrien n’ont pas été fructueux. C’est le cas notamment pour la ribavirine, un analogue de la guanosine à large spectre antiviral [67] , pour des composés dérivés de la ribavirine (EICAR, EICNR) [68] , pour le favipiravir, un inhibiteur de virus à ARN à large spectre [69] , pour la pyriméthamine, une molécule utilisée dans le traitement de maladies à protozoaires comme la toxoplasmose ou le paludisme [70] , ou la pour la ranpirnase, une ribonucléase utilisée comme agent antitumoral [71] .…”

Section: Guérir De La Rage ? Vers Un Changement De Paradigme Dans Le unclassified

Nouveaux aspects de la lutte contre la rage

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La rage est encore aujourd’hui responsable d’environ 60 000 décès humains par an, principalement dans les populations démunies en Afrique et en Asie. Pourtant, depuis le développement du premier vaccin par Louis Pasteur, il y a 130 ans, les mesures prophylactiques se sont considérablement améliorées et allégées. Elles sont désormais composées du vaccin associé à des immunoglobulines antirabiques d’origine équine ou humaine purifiées. Mais, d’une manière générale, les protocoles de prophylaxie post-exposition sont longs et coûteux et les immunoglobulines, qui servent à la sérothérapie associée, sont chères et peu accessibles dans les pays en voie de développement. Enfin, la rage chez l’Homme reste incurable lorsque les symptômes apparaissent, voire même lorsque les patients sont pris en charge trop tardivement pendant la période d’incubation. Dans ces deux cas, des approches, qui laissent espérer un changement de paradigme au bénéfice des populations exposées, ont été développées. Enfin, les campagnes de vaccination antirabique de masse des chiens, qui constituent la mesure de prévention de la rage chez l’Homme la plus efficace et la moins coûteuse, se heurtent à des difficultés d’implémentation et présentent, parfois, une efficacité modérée. À ce titre, l’identification et l’analyse des moteurs épidémiologiques, conditionnant la circulation du virus dans les populations canines, permettent de mieux comprendre les points clés du contrôle qui doivent être associés à ces campagnes.

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Antiviral Ranpirnase TMR-001 Inhibits Rabies Virus Release and Cell-to-Cell Infection In Vitro

Cited by 12 publications

References 35 publications

Artesunate and Dihydroartemisinin Inhibit Rabies Virus Replication

Artesunate and Dihydroartemisinin Inhibit Rabies Virus Replication

Strengths and Challenges of Secretory Ribonucleases as AntiTumor Agents

Nouveaux aspects de la lutte contre la rage

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