Human cytomegalovirus (CMV) susceptibility to currently approved antiviral drugs does not impact on CMV terminase complex polymorphism

Pilorgé, Léa; Burrel, Sonia; Ait-Arkoub, Zaïna; Agut, Henri; Boutolleau, David

doi:10.1016/j.antiviral.2014.08.014

Cited by 25 publications

(12 citation statements)

References 22 publications

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“…Accordingly, these results support our earlier hypothesis that naturally occurring polymorphisms associated with reduced letermovir sensitivity are very unlikely in HCMV field isolates (Goldner et al, 2014). Importantly, this hypothesis was recently supported by a publication by Pilorge and colleagues who likewise demonstrated a low natural polymorphism rate in ORF UL56 of 63 clinical HCMV strains, none of which were in the letermovir resistance region AA 230-370 (Pilorge et al, 2014).…”

Section: Introductionsupporting

confidence: 80%

Phenotypic characterization of two naturally occurring human Cytomegalovirus sequence polymorphisms located in a distinct region of ORF UL56 known to be involved in in vitro resistance to letermovir

2015

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Section: Introductionsupporting

confidence: 80%

Phenotypic characterization of two naturally occurring human Cytomegalovirus sequence polymorphisms located in a distinct region of ORF UL56 known to be involved in in vitro resistance to letermovir

2015

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“…Member of the new antiviral class of quinazolines, it acts after viral DNA synthesis by inhibiting the subunit protein pUL56 that, together with pUL89, is a key element of the enzyme complex named terminase, [72,73] directly involved in the cleavage and package of viral DNA chains in the virionic capside [74,75]. Because of its distinct mechanism of action, it does not show cross-resistance with other antiviral drugs and there are reports of clinically relevant activity against GCV-, FOS-and CDF-resistant CMV strains [76,77].…”

Section: Letermovir -The Terminasetormentioning

confidence: 99%

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

Madon

Giaccone

Festuccia

et al. 2016

Expert Review of Hematology

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“…The CMV terminase complex is comprised of two proteins, pUL89 and pUL56, that interact synergistically. 15 , 16 As noted earlier, the main function of the terminase complex is to cleave CMV concatemers into single units of functional CMV monomers. 17 , 18 The terminase complex further interacts with portal (viral capsid) proteins to facilitate DNA translocation into the capsid.…”

Section: Biology As Targets For Antiviral Therapymentioning

confidence: 95%

“…These compounds, however, are currently not undergoing further clinical development. 16 , 18 , 38 , 39 …”

Section: Letermovir and Inhibitors Of The CMV Terminase Complexmentioning

confidence: 99%

Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus

Melendez¹,

Razonable²

2015

IDR

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Infection with cytomegalovirus is prevalent in immunosuppressed patients. In solid organ transplant and hematopoietic stem cell transplant recipients, cytomegalovirus infection is associated with high morbidity and preventable mortality. Prevention and treatment of cytomegalovirus with currently approved antiviral drugs is often associated with side effects that sometimes preclude their use. Moreover, cytomegalovirus has developed mutations that confer resistance to standard antiviral drugs. During the last decade, there have been calls to develop novel antiviral drugs that could provide better options for prevention and treatment of cytomegalovirus. Letermovir (AIC246) is a highly specific antiviral drug that is currently undergoing clinical development for the management of cytomegalovirus infection. It acts by inhibiting the viral terminase complex. Letermovir is highly potent in vitro and in vivo against cytomegalovirus. Because of a distinct mechanism of action, it does not exhibit cross-resistance with other antiviral drugs. It is predicted to be active against strains that are resistant to ganciclovir, foscarnet, and cidofovir. To date, early-phase clinical trials suggest a very low incidence of adverse effects. Herein, we present a comprehensive review on letermovir, from its postulated novel mechanism of action to the results of most recent clinical studies.

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Human cytomegalovirus (CMV) susceptibility to currently approved antiviral drugs does not impact on CMV terminase complex polymorphism

Cited by 25 publications

References 22 publications

Phenotypic characterization of two naturally occurring human Cytomegalovirus sequence polymorphisms located in a distinct region of ORF UL56 known to be involved in in vitro resistance to letermovir

Phenotypic characterization of two naturally occurring human Cytomegalovirus sequence polymorphisms located in a distinct region of ORF UL56 known to be involved in in vitro resistance to letermovir

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus

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