Ether Lipid Ester Derivatives of Cidofovir Inhibit Polyomavirus BK Replication In Vitro

Randhawa, Parmjeet; Farasati, Noush Afarin; Shapiro, Ron; Hostetler, Karl Y.

doi:10.1128/aac.50.4.1564-1566.2006

Cited by 76 publications

(62 citation statements)

References 21 publications

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“…Esterification of cidofovir with hexadecyloxypropyl, octadecyloxyethyl or oleyloxyethyl groups results in up to 3-log lowering of EC 50 and markedly increased selectivity index in vitro. Oral bioavailability and reduced nephrotoxicity are additional potential advantages of these derivatives over unmodified cidofovir (35). A cautiously conducted controlled clinical trial of these compounds in the management of BKVN appears to be warranted.…”

Section: Treatmentmentioning

confidence: 99%

BK Virus Infection in Transplant Recipients: An Overview and Update

Randhawa

Brennan

2006

American Journal of Transplantation

189

152

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BK virus infection after kidney transplantation has been a subject of great interest in the past decade. This article traces the discovery of BK virus and the subsequent development of our knowledge about this emerging pathogen. The pathobiology of the virus is summarized with particular reference to epidemiology, interactions with host cell receptors, cell entry, cytoplasmic trafficking and targeting of the viral genome to the nucleus. This is followed by a discussion of clinical features, laboratory monitoring and therapeutic strategies. Finally, we present potential cellular mechanisms that explain the basis of virus-mediated damage to the human kidney.

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Section: Treatmentmentioning

confidence: 99%

BK Virus Infection in Transplant Recipients: An Overview and Update

Randhawa

Brennan

2006

American Journal of Transplantation

189

152

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“…Cidofovir (CDV) is one such compound that has activity against many viruses, and recently, alkoxyalkyl ester prodrug forms of CDV have been reported to be active at concentrations up to 3 orders of magnitude lower than the active concentrations of the parent compound (36). The compound CMX001 (hexadecyloxypropyl CDV) has excellent activity against adenoviruses, orthopoxviruses, and polyomaviruses, as well as the herpesviruses (13,18,32,36). Equally important is the increased oral bioavailability conferred by the alkoxyalkyl substituent (1,3,17,30), which appears to reduce drug exposure in the mouse kidney and may reduce the potential of the drug for renal toxicity (4).…”

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confidence: 99%

Inhibition of Herpesvirus Replication by 5-Substituted 4′-Thiopyrimidine Nucleosides

Prichard

Quenelle

Hartline

et al. 2009

Antimicrob Agents Chemother

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A series of 4-thionucleosides were synthesized and evaluated for activities against orthopoxviruses and herpesviruses. We reported previously that one analog, 5-iodo-4-thio-2-deoxyuridine (4-thioIDU), exhibits good activity both in vitro and in vivo against two orthopoxviruses. This compound also has good activity in cell culture against many of the herpesviruses. It inhibited the replication of herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus with 50% effective concentrations (EC 50 s) of 0.1, 0.5, and 2 M, respectively. It also inhibited the replication of human cytomegalovirus (HCMV) with an EC 50 of 5.9 M but did not selectively inhibit Epstein-Barr virus, human herpesvirus 6, or human herpesvirus 8. While acyclovir-resistant strains of HSV-1 and HSV-2 were comparatively resistant to 4-thioIDU, it retained modest activity (EC 50 s of 4 to 12 M) against these strains. Some ganciclovir-resistant strains of HCMV also exhibited reduced susceptibilities to the compound, which appeared to be related to the specific mutations in the DNA polymerase, consistent with the observed incorporation of the compound into viral DNA. The activity of 4-thioIDU was also evaluated using mice infected intranasally with the MS strain of HSV-2. Although there was no decrease in final mortality rates, the mean length of survival after inoculation increased significantly (P < 0.05) for all animals receiving 4-thioIDU. The findings from the studies presented here suggest that 4-thioIDU is a good inhibitor of some herpesviruses, as well as orthopoxviruses, and this class of compounds warrants further study as a therapy for infections with these viruses.

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“…This side effect is apparently abrogated by lipid conjugation in BCV (12). In addition, comparative in vitro studies show a 24-to 400-fold reduction in the concentrations required to give 50 and 90% inhibition of viral replication (EC 50 and EC 90 ) (19,27). This has been attributed to the rapid cellular uptake conferred by the lipid moiety (27).…”

mentioning

confidence: 90%

“…Calculation of the effective concentrations and the selective indices. The Microsoft Excel-based plug-in XLfit was used for curve fitting to determine the 50% and 90% effective concentrations (EC 50 and EC 90 ) and the 50% and 90% cytostatic or cytotoxic concentration (CC 50 and CC 90 ) and their respective 95% confidence intervals. These results were used to calculate the selective indices (SI 50 and SI 90 ).…”

Section: Methodsmentioning

confidence: 99%

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Brincidofovir (CMX001) Inhibits BK Polyomavirus Replication in Primary Human Urothelial Cells

Tylden

Hirsch

Rinaldo

2015

Antimicrob Agents Chemother

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e BK polyomavirus (BKPyV)-associated hemorrhagic cystitis (PyVHC) complicates 5 to 15% of allogeneic hematopoietic stem cell transplantations. Targeted antivirals are still unavailable. Brincidofovir (BCV; previously CMX001) has shown inhibitory activity against diverse viruses, including BKPyV in a primary human renal tubule cell culture model of polyomavirus-associated nephropathy. We investigated the effects of BCV in BKPyV-infected and uninfected primary human urothelial cells (HUCs), the target cells of BKPyV in PyVHC. The BCV concentrations causing 50 and 90% reductions (EC 50 and EC 90 ) in the number of intracellular BKPyV genome equivalents per cell (icBKPyV) were 0.27 M and 0.59 M, respectively. At 0.63 M, BCV reduced viral late gene expression by 90% and halted progeny release. Preinfection treatment for only 24 h reduced icBKPyV similarly to treatment from 2 to 72 h postinfection, while combined pre-and postinfection treatment suppressed icBKPyV completely. After investigating BCV's effects on HUC viability, mean selectivity indices at 50 and 90% inhibition (SI 50 and SI 90 ) calculated for cellular DNA replication were 2.7 and 2.9, respectively, those for mitochondrial activity were 8.9 and 10.4, those for total ATP were 8.6 and 8.2, and those for membrane integrity were 25.9 and 16.7. The antiviral and cytostatic effects, but less so the cytotoxic effects, were inversely related to cell density. The cytotoxic effects at concentrations of >10 M were rapid and likely related to BCV's lipid moiety. After carefully defining the antiviral, cytostatic, and cytotoxic properties of BCV in HUCs, we conclude that a preemptive or prophylactic approach in PyVHC is likely to give the best results.T he ubiquitous and usually quiescent BK polyomavirus (BKPyV) causes polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) following kidney and hematopoietic stem cell transplantation (HSCT), respectively (1).PyVHC afflicts 5 to 15% of HSCT patients after engraftment (2-5). The pathogenesis of PyVHC is incompletely characterized but is believed to involve initial iatrogenic damage to the bladder mucosa during pretransplantation conditioning, which is subsequently aggravated by lytic BKPyV replication in urothelial cells in the absence of immune surveillance. This leads to exposure of both viral and host epitopes to the foreign, engrafting lymphoid cells and may contribute to graft-versus-host disease (GVHD) (6-10). Inflammation and the resultant denudation of the urothelium cause hemorrhagic cystitis ranging from microhematuria to macrohematuria, clot-related urinary retention, and postrenal failure (reviewed in reference 5).PyVAN occurs in transplanted kidneys in 1 to 10% of recipients and often results in graft loss via a combination of lytic and inflammatory destruction of the renal parenchyma (2, 5). The initial reactivation signal is unknown, but mathematical modeling supports initial reactivation in the tubular epithelial compartment, followed by viral efflux with amplification in the uroth...

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Ether Lipid Ester Derivatives of Cidofovir Inhibit Polyomavirus BK Replication In Vitro

Cited by 76 publications

References 21 publications

BK Virus Infection in Transplant Recipients: An Overview and Update

BK Virus Infection in Transplant Recipients: An Overview and Update

Inhibition of Herpesvirus Replication by 5-Substituted 4′-Thiopyrimidine Nucleosides

Brincidofovir (CMX001) Inhibits BK Polyomavirus Replication in Primary Human Urothelial Cells

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