Pharmacokinetics-Pharmacodynamics of the Helicase-Primase Inhibitor Pritelivir following Treatment of Wild-Type or Pritelivir-Resistant Virus Infection in a Murine Herpes Simplex Virus 1 Infection Model

A Preclinical Model for Studying Herpes Simplex Virus Infection

“…To inhibit viral replication, viral DNA-targeting chemotherapeutics such as nucleoside analogues (e.g., acyclovir, penciclovir, valacyclovir, and famciclovir) are widely used either as episodic therapy for a short period or as daily suppressive therapy for months or years, even though latent virus cannot be eradicated (Biswas et al, 2014). Nucleoside analogues inhibit viral DNA polymerase after activation by viral thymidine kinase.…”

“…Nucleoside analogues inhibit viral DNA polymerase after activation by viral thymidine kinase. HSV resistance to nucleoside analogues has been reported as being due to mutations in viral thymidine kinase or polymerase resulting in a loss or alterations in substrate specificity (Strasfeld and Chou, 2010), and this is recognized as a clinical problem among immunocompromised patients (Biswas et al, 2014;Krawczyk et al, 2013). Although in nucleoside analogue-resistant cases thymidine kinase-independent drugs such as the viral DNA polymerase inhibitors foscarnet and cidofovir can be administered, these compounds frequently have severe toxic effects, particularly in patients with comorbidities (Kim et al, 2015).…”

“…Although in nucleoside analogue-resistant cases thymidine kinase-independent drugs such as the viral DNA polymerase inhibitors foscarnet and cidofovir can be administered, these compounds frequently have severe toxic effects, particularly in patients with comorbidities (Kim et al, 2015). To fulfill the request for effective alternatives to nucleoside analogue inhibitors and to counteract resistance, several compounds have been screened for their antiviral activity (Biswas et al, 2014). Moreover, potential alternative therapeutic vaccines are under investigation, but limited protections to viral shedding and lesion development have been shown so far (Birkmann and Zimmermann, 2016).…”

“…Furthermore, helicase-primase inhibitors (i) activate in the absence of viral or cellular enzymes such as thymidine kinase, (ii) are equally effective against HSV-1 and HSV-2, (iii) are orally bioavailable, (iv) exhibit higher potency than therapeutic vaccines, and (v) lack crossresistance to nucleosides (Birkmann and Zimmermann, 2016). Pritelivir (PTV, BAY-57-1293, AIC316) is a member of the group of helicase-primase inhibitors and shows a superior pharmacological profile compared with standard HSV treatment (Betz et al, 2002;Biswas et al, 2014;Crute et al, 2002;Kleymann et al, 2002). Recently, it has successfully finished a phase 2 clinical trial (Wald et al, 2014(Wald et al, , 2016.…”

Characterization of the C-Terminal Nuclease Domain of Herpes Simplex Virus pUL15 as a Target of Nucleotidyltransferase Inhibitors

“…The helicase-primase inhibitor pritelivir also provides a new class of antiviral compounds distinct from those in current use. 8 Finally, Krawczyk et al have suggested the use of humanized antibodies to counter drug-resistant HSV. 9 On the basis of the effectiveness of combination antiretroviral therapy in treating HIV infection, a cocktail of agents for HSV showing acceptable pharmacodynamic profiles and distinct molecular targets would be expected to significantly reduce viral load and delay acquisition of drug resistance.…”