Inhibition of Herpes Simplex Virus Type 1 by the Experimental Immunosuppressive Agent Leflunomide1

Knight, Deborah; Hejmanowski, Ashley Quintin; Dierksheide, Julie; Williams, James W.; Chong, Anita S.; Waldman, W. James

doi:10.1097/00007890-200101150-00031

Cited by 93 publications

(78 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…One previous anecdotal report suggested a response to leflunomide and cidofovir in a transplant patient with CMV resistant to ganciclovir and foscarnet (J Williams, personal communication). Leflunomide also appears to have antiviral activity against HSV as well, 33 and this patient's refractory oral HSV ulceration did improve on leflunomide therapy. This patient's CMV DNAemia did clear transiently on leflunomide and foscarnet.…”

Section: Discussionmentioning

confidence: 77%

Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection

Avery

Bolwell

Yen‐Lieberman

et al. 2004

Bone Marrow Transplant

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 77%

Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection

Avery

Bolwell

Yen‐Lieberman

et al. 2004

Bone Marrow Transplant

View full text Add to dashboard Cite

“…In any scenario, inhibition of the de novo pathway would result in an antiviral phenotype by restricting the virus of pyrimidines necessary for replication. There are multiple in vitro data implicating de novo pyrimidine biosynthesis pathway as an antiviral candidate for adenovirus, vaccinia virus, influenza B virus, paramyxovirus, picornavirus, reovirus, herpes viruses, and BK virus (36)(37)(38)(39). There are also reports of efficacy studies in animal models with banzi virus, influenza B virus, and vaccinia virus (36) that showed either a lack of or very limited efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…There are also reports of efficacy studies in animal models with banzi virus, influenza B virus, and vaccinia virus (36) that showed either a lack of or very limited efficacy. Clinical trials in humans were also reported for HIV, CMV, and BK virus (38,(40)(41)(42)(43), with no conclusive results. It is reported that mean levels of circulating uridine in man are approximately 6 μM (44), spanning a range between 2.6 μM (45) and 21 μM (46).…”

Section: Discussionmentioning

confidence: 99%

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Bonavia¹,

Franti²,

Keaney³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.

show abstract

“…Leflunomide has been shown to prevent replication of HIV-1 (15) and herpesviruses (16,17) in vitro. Because our previous studies had demonstrated that the inhibitory effect of RSV on AFC requires active viral replication (4), it was possible that the beneficial effects of leflunomide might simply be a consequence of inhibition of replication by this drug.…”

Section: Effect Of Nucleotide Synthesis Inhibition On Rsv Replicationmentioning

confidence: 99%

Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus

Davis

Lazarowski

Hickman-Davis

et al. 2006

Am J Respir Crit Care Med

View full text Add to dashboard Cite

Rationale: Previously, we demonstrated that intranasal infection of BALB/c mice with respiratory syncytial virus (RSV) resulted in an early 40% reduction in alveolar fluid clearance (AFC), an effect mediated via P2Y purinergic receptors. Objectives: To confirm that RSV-induced inhibition of AFC is mediated by uridine triphosphate (UTP), and to demonstrate that inhibition of de novo pyrimidine synthesis with leflunomide prevents increased UTP release after RSV infection, and thereby also prevents inhibition of AFC by RSV. Methods: BALB/c mice were infected intranasally with RSV strain A2. AFC was measured in anesthetized, ventilated mice by instillation of 5% bovine serum albumin into the dependent lung. Some mice were pretreated with leflunomide or 6-mercaptopurine. Measurements and Main Results: RSV-mediated inhibition of AFC is associated temporally with a 20-nM increase in UTP and ATP content of bronchoalveolar lavage fluid, hypoxemia, and altered nasal potential difference. RSV-mediated nucleotide release, AFC inhibition, and physiologic sequelae thereof can be prevented by pretreatment of mice with the de novo pyrimidine synthesis inhibitor leflunomide, which is not toxic to the mice, and which does not affect RSV replication in the lungs. In contrast, pretreatment of mice with 6-mercaptopurine, an inhibitor of de novo purine synthesis, has no beneficial effect on AFC or other indicators of disease progression. Finally, RSV-mediated inhibition of AFC is prevented by volumeregulated anion channel inhibitors. Conclusion: Pyrimidine synthesis or release pathways may provide novel therapeutic targets to counter the pathophysiologic sequelae of impaired AFC in RSV disease.Keywords: ion transport; paramyxovirus infections; pneumonia, viral; pulmonary edemaThe dominant ion transport process of the alveolar epithelium is active movement of Na ϩ ions from the airspace lining fluid to the interstitium (1). This creates an osmotic gradient, causing water to follow passively. This process of alveolar fluid clearance (AFC) is crucial to efficient gas exchange. Importantly, patients with acute lung injury with intact AFC have lower morbidity and mortality than those with compromised AFC (2).Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in infants and children worldwide (3), but its pathogenesis remains poorly understood. Previously, we demonstrated that infection of BALB/c mice with RSV results in reduced AFC at early time points after infection, and inferred that RSV-mediated inhibition of AFC 2 d after infection was mediated by uridine triphosphate (UTP), acting on P2Y receptors (P2YRs) on lung epithelial cells (4). The aim of the current study was to confirm the central role of UTP in mediating the inhibitory effects of RSV on AFC, and to demonstrate that pharmacologic inhibition of de novo pyrimidine synthesis with leflunomide prevents increased UTP release after RSV infection, and thereby also prevents inhibition of AFC by RSV. Furthermore, we demonstrated that blockag...

show abstract

Inhibition of Herpes Simplex Virus Type 1 by the Experimental Immunosuppressive Agent Leflunomide1

Abstract: These findings, in demonstrating that leflunomide exerts antiviral activity against HSV-1 by mechanisms similar to those we have previously shown with cytomegalovirus, imply that this agent may possess broad spectrum activity against other herpesviruses.

Cited by 93 publications

References 13 publications

Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection

Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus

Contact Info

Product

Resources

About