Brincidofovir: Understanding its Unique Profile and Potential Role Against Adenovirus and Other Viral Infections

Alvarez-Cardona, Julio J.; Whited, Laura; Chemaly, Roy F.

doi:10.2217/fmb-2019-0288

Cited by 38 publications

(33 citation statements)

References 54 publications

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“…Additionally, immunocompromised individuals, such as transplant recipients, are at particular risk for severe illness or death from numerous HAdVs, including HAdV-C, -A, and -B (11,22). Aside from cidofovir, a nucleotide analogue approved for cytomegalovirus-induced retinitis, and the cidofovir derivative brincidofovir, there are no antiviral drugs with clinically relevant activity against HAdV (22,23). Notably, HAdV gene expression, genome replication, and virion assembly all take place within the nucleus, and many of its gene products carry out crucial functions in this compartment to enhance its viral replication cycle (24,25).…”

mentioning

confidence: 99%

Inhibition of Human Adenovirus Replication by the Importin α/β1 Nuclear Import Inhibitor Ivermectin

King

Tessier

Dodge

et al. 2020

J Virol

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Human adenoviruses (HAdV) are ubiquitous within the human population and comprise a significant burden of respiratory illnesses worldwide. Pediatric and immunocompromised individuals are at particular risk for developing severe disease, however, no approved antiviral therapies specific to HAdV exist. Ivermectin is an FDA-approved broad spectrum antiparasitic drug that also exhibits antiviral properties against a diverse range of viruses. Its proposed function is inhibiting the classical protein nuclear import pathway mediated by importin-α (Imp-α) and -β1 (Imp-β1). Many viruses, including HAdV, rely on this host pathway for transport of viral proteins across the nuclear envelope. In this study we show that ivermectin inhibits HAdV-C5 early gene transcription, early and late protein expression, genome replication, and production of infectious viral progeny. Similarly, ivermectin inhibits genome replication of HAdV-B3, a clinically important pathogen responsible for numerous recent outbreaks. Mechanistically, we show that ivermectin disrupts binding of the viral E1A protein to Imp-α without affecting the interaction between Imp-α and Imp-β1. Our results further extend ivermectin's broad antiviral activity and provide a mechanistic underpinning for its mode of action as an inhibitor of cellular Imp-α/β1 mediated nuclear import. IMPORTANCE Human adenoviruses (HAdVs) represent a ubiquitous and clinically important pathogen without an effective antiviral treatment. HAdV infections typically cause mild symptoms, however individuals such as children, those with underlying conditions, and those with compromised immune systems can develop severe disseminated disease. Our results demonstrate that ivermectin, an FDA approved antiparasitic agent, is effective at inhibiting replication of several HAdV types in vitro. This is in agreement with the growing body of literature suggesting ivermectin has broad antiviral activity. This study expands our mechanistic knowledge of ivermectin by showing that ivermectin targets the ability of Imp-α to recognize nuclear localization sequences, without effecting the Imp-α/β1 interaction. These data also exemplify the applicability of targeting host factors upon which viruses rely as a viable antiviral strategy.

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confidence: 99%

Inhibition of Human Adenovirus Replication by the Importin α/β1 Nuclear Import Inhibitor Ivermectin

King

Tessier

Dodge

et al. 2020

J Virol

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“…Other investigational drugs that target other viral mechanisms have been tested with variable results [15]. Brincidofovir, which also inhibits the HCMV DNA polymerase, failed in a phase III study evaluating its prophylactic effect in stem cell transplant patients [61]. Maribavir failed to show an effect as a prophylactic drug, but is under evaluation for pre-emptive treatment and treatment of established HCMV disease (NCT 02927067 and NCT02931539).…”

Section: Discussionmentioning

confidence: 99%

The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection

Landázuri

Gorwood

Terelius

et al. 2021

Cells

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Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in immunocompromised patients and a major etiological factor for congenital birth defects in newborns. Ganciclovir and its pro-drug valganciclovir are the preferred drugs in use today for prophylaxis and treatment of viremic patients. Due to long treatment times, patients are at risk for developing viral resistance to ganciclovir and to other drugs with a similar mechanism of action. We earlier found that the endothelin receptor B (ETBR) is upregulated during HCMV infection and that it plays an important role in the life cycle of this virus. Here, we tested the hypothesis that ETBR blockade could be used in the treatment of HCMV infection. As HCMV infection is specific to humans, we tested our hypothesis in human cell types that are relevant for HCMV pathogenesis; i.e., endothelial cells, epithelial cells and fibroblasts. We infected these cells with HCMV and treated them with the ETBR specific antagonist BQ788 or ETR antagonists that are approved by the FDA for treatment of pulmonary hypertension; macitentan, its metabolite ACT-132577, bosentan and ambrisentan, and as an anti-viral control, we used ganciclovir or letermovir. At concentrations expected to be relevant in vivo, macitentan, ACT-132577 and BQ788 effectively inhibited productive infection of HCMV. Of importance, macitentan also inhibited productive infection of a ganciclovir-resistant HCMV isolate. Our results suggest that binding or signaling through ETBR is crucial for viral replication, and that selected ETBR blockers inhibit HCMV infection.

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“…The limited bioavailability of CDV following oral administration contributed to the synthesis of brincidofovir (BCDV), which contains a synthetic, acyclic monophosphate nucleotide analogue (cidofovir) conjugated to a lipid (3-hexadecyloxy1-propanol) via a phosphonate group. Conjugation with a lipid molecule improves BCDV delivery to the target cells and also significantly reduces the nephrotoxicity compared to CDV [ 52 , 88 ].…”

Section: Antiviral Drugsmentioning

confidence: 99%

40 Years after the Registration of Acyclovir: Do We Need New Anti-Herpetic Drugs?

Majewska

Młynarczyk-Bonikowska

2022

IJMS

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Herpes simplex virus types 1 and 2 HSV1 and 2, namely varicella-zoster VZV and cytomegalovirus CMV, are among the most common pathogens worldwide. They remain in the host body for life. The course of infection with these viruses is often asymptomatic or mild and self-limiting, but in immunocompromised patients, such as solid organ or bone marrow transplant recipients, the course can be very severe or even life-threatening. Unfortunately, in the latter group, the highest percentage of infections with strains resistant to routinely used drugs is observed. On the other hand, frequent recurrences of genital herpes can be a problem even in people with normal immunity. Genital herpes also increases the risk of acquiring sexually transmitted diseases, including HIV infection and, if present in pregnant women, poses a risk to the fetus and newborn. Even more frequently than herpes simplex, congenital infections can be caused by cytomegalovirus. We present the most important anti-herpesviral agents, the mechanisms of resistance to these drugs, and the associated mutations in the viral genome. Special emphasis was placed on newly introduced drugs such as maribavir and brincidofovir. We also briefly discuss the most promising substances in preclinical testing as well as immunotherapy options and vaccines currently in use and under investigation.

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Brincidofovir: Understanding its Unique Profile and Potential Role Against Adenovirus and Other Viral Infections

Cited by 38 publications

References 54 publications

Inhibition of Human Adenovirus Replication by the Importin α/β1 Nuclear Import Inhibitor Ivermectin

Inhibition of Human Adenovirus Replication by the Importin α/β1 Nuclear Import Inhibitor Ivermectin

The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection

40 Years after the Registration of Acyclovir: Do We Need New Anti-Herpetic Drugs?

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