In vitro evaluation of current and novel antivirals in combination against human cytomegalovirus

O’Brien, Myles; Markovich, Kylie C.; Selleseth, Dean W.; DeVita, Alexa V.; Sethna, Phiroze; Gentry, Brian G.

doi:10.1016/j.antiviral.2018.08.015

Cited by 22 publications

(9 citation statements)

References 56 publications

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“…Previous studies indicated that GS5806, BMS433771 and Ziresovir interfere with RSV F protein through a same mode of inhibition, targeting the same domain (between HR1 and HR2) [6]. It is likely that the molecules inhibitors compete with each other when interaction with F protein, resulting in the observed antagonism effect [31,33]. Interestingly, the combination of cyclopamine with any other compound yielded no more additive antiviral effects, and CPM-RSV604 showed a strong antagonistic effect against RSV in vitro.…”

Section: Discussionmentioning

confidence: 98%

“…Three combinations between fusion inhibitors showed strong antagonistic effects against RSV in vitro. Synergy can be expected if the two compounds being investigated target different steps of virus replication [31]. Previous studies indicated that GS5806, BMS433771 and Ziresovir interfere with RSV F protein through a same mode of inhibition, targeting the same domain (between HR1 and HR2) [6].…”

Section: Discussionmentioning

confidence: 99%

“…A therapeutic combination strategy for RSV treatment might be an attractive option to overcome drug-associated side effects and antiviral resistance development [28,29]. Similar combination strategies are effective against HCV [30], HCMV [31,32], EV71 [33], influenza [34,35], and ZIKV [36]. As a proof-of-concept of combination therapeutic strategies against RSV, two-compound combinations of fusion inhibitors (GS5806, Ziresovir, BMS433771) and RdRp inhibitors (ALS8176, RSV604, CPM) were evaluated in HEp-2 cells with a firefly luciferase gene inserted into a recombinant RSV strain as described recently, and inhibition efficacy of antiviral combinations were measured by luciferase activity and quantitative PCR.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro

et al. 2021

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Respiratory syncytial virus (RSV) is a major pathogen that causes severe lower respiratory tract infection in infants, the elderly and the immunocompromised worldwide. At present no approved specific drugs or vaccines are available to treat this pathogen. Recently, several promising candidates targeting RSV entry and multiplication steps are under investigation. However, it is possible to lead to drug resistance under the long-term treatment. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we tested in vitro two-drug combinations of fusion inhibitors (GS5806, Ziresovir and BMS433771) and RNA-dependent RNA polymerase complex (RdRp) inhibitors (ALS8176, RSV604, and Cyclopamine). The statistical program MacSynergy II was employed to determine synergism, additivity or antagonism between drugs. From the result, we found that combinations of ALS8176 and Ziresovir or GS5806 exhibit additive effects against RSV in vitro, with interaction volume of 50 µM2% and 31 µM2% at 95% confidence interval, respectively. On the other hand, all combinations between fusion inhibitors showed antagonistic effects against RSV in vitro, with volume of antagonism ranging from −50 µM2 % to −176 µM2 % at 95% confidence interval. Over all, our results suggest the potentially therapeutic combinations in combating RSV in vitro could be considered for further animal and clinical evaluations.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro

et al. 2021

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“…[22][23][24] LMV is approximately 1000-fold more potent than ganciclovir and retains activity against CMV virus strains resistant to currently approved antivirals. [22][23][24][25] Importantly, LMV neither inhibits CMV DNA replication nor expression of late viral proteins in infected cells, rather it dramatically impairs nuclear egress and eventual release of infectious virions from cells, thus severely limiting subsequent rounds of CMV replication in adjacent or distant uninfected cells. 22,23 Remarkably, LMV activity associates with the accumulation of dense bodies (subviral infectious particles) in the cytoplasm of infected cells, which may drive the expansion of CMV-specific T cells.…”

Section: Mechanism Of Action Of Lmvmentioning

confidence: 99%

Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review

Solano

Giménez

Albert

et al. 2023

Journal of Medical Virology

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On November 7, 2017, the US Food and Drug Administration approved the use of letermovir (LMV) for prophylaxis of cytomegalovirus (CMV) infection in adult CMV‐seropositive allogeneic stem cell transplant recipients. After 6 years of use, a large body of real‐world experience has been accumulated that validates the Phase III clinical trial results, in which LMV was shown to significantly reduce the risk of clinically significant CMV infection—defined as CMV end‐organ disease or CMV DNAemia requiring pre‐emptive antiviral therapy (PET)—and increase survival up to Week 24 after treatment inception. Notwithstanding, several issues still need to be settled, thus further investigation is required. First, since viral DNA may accumulate as a result of LMV‐driven abortive CMV infection, what is the optimal viral load threshold in the blood that would prompt LMV prophylaxis interruption and PET inception? Should this be adapted to the patient's risk? Second, what is the impact of LMV prophylaxis on the reconstitution of functional CMV‐specific T‐cell responses? Would it be a wise approach to individually tailor the duration of LMV treatment according to the number of peripheral blood CMV‐specific T cells at the end of regular prophylaxis? Third, how frequently do LMV‐resistant strains arise while patients are on LMV prophylaxis and how could this be minimized? Here, we discuss the literature addressing these topics.

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“…In one study, the combination of letermovir with the DNA polymerase inhibitors ganciclovir, foscarnet, and cidofovir demonstrated only an additive, not synergistic, effect in vitro [44]. However, another study found a small degree of synergy between letermovir and brincidofovir, an oral prodrug of cidofovir [45]. More work, both clinical and in vitro, is required to address the potential utility of letermovir-based combination therapy.…”

Section: Further Defining the Benefit Of Letermovir Prophylaxis Inmentioning

confidence: 99%

Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy

Hakki

2020

Curr Hematol Malig Rep

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Purpose of Review CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often limited by toxicities and resistance. Agents with novel mechanisms and favorable toxicity profiles are critically needed. We review recent developments in CMV antivirals and immune-based approaches to mitigating CMV infection. Recent Findings Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients. Maribavir, an inhibitor of the CMV UL97 kinase, is currently in two phase 3 treatment studies. Adoptive immunotherapy using third-party T cells has proven safe and effective in preliminary studies. Vaccine development continues, with several promising candidates currently under study. Summary No longer limited to DNA polymerase inhibitors, the prevention and treatment of CMV infections in the HCT recipient is a rapidly evolving field which should translate into improvements in CMV-related outcomes.

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In vitro evaluation of current and novel antivirals in combination against human cytomegalovirus

Cited by 22 publications

References 56 publications

Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro

Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro

Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review

Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy

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