No Evidence of Pritelivir Resistance Among Herpes Simplex Virus Type 2 Isolates After 4 Weeks of Daily Therapy
| Autor: | Thomas Goldner, Craig A. Magaret, Susanne Stoelben, Burkhard Timmler, Alexander Birkmann, Lawrence Corey, Holger Zimmermann, Anna Wald, Kurt Diem, Jia Jin Kee, Paul T. Edlefsen, Helga Ruebsamen-Schaeff, Meei Li Huang, Terri Warren |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male Enzyme complex DNA polymerase Pyridines Herpesvirus 2 Human 030106 microbiology medicine.disease_cause Antiviral Agents Virus 03 medical and health sciences Viral Proteins Major Articles and Brief Reports Drug Resistance Viral medicine Immunology and Allergy Humans helicase-primase inhibitor Viral shedding Sulfonamides Herpes Genitalis drug resistance Nucleoside analogue biology Sequence Analysis DNA Virology Thiazoles 030104 developmental biology Infectious Diseases Herpes simplex virus Thymidine kinase Mutation Viruses biology.protein Female Primase herpes simplex virus 2 viral genomics pritelivir medicine.drug |
| Zdroj: | The Journal of Infectious Diseases |
| ISSN: | 1537-6613 |
| Popis: | Pritelivir (also known as BAY 57–1293 and AIC316) belongs to a new class of antiviral compounds, the helicase-primase inhibitors (HPIs), that prevent the de novo synthesis of virus DNA through inhibition of the helicase-primase complex [1]. Functionally, both UL5 and UL52, together with the accessory protein UL8, form the helicase-primase enzyme complex, the molecular target of pritelivir [2]. Unlike nucleoside analogues, which are currently the mainstay of therapy for herpes simplex virus (HSV) infections, pritelivir does not require activation by viral thymidine kinase within an HSV-infected cell. HSV infections resistant to nucleoside analogues are rare in immunocompetent persons, but their frequency is increased in immunocompromised patients [3]. Mutations mediating resistance to nucleoside analogs are located in the gene encoding the thymidine kinase and/or the gene encoding the DNA polymerase. All resistance-mediating mutations to pritelivir identified so far in vitro are located either at a single amino acid position in the viral UL52 primase (amino acid 906) or within/downstream of the fourth functional motif of the viral UL5 helicase (the conserved helicase motif; amino acids 341–355; Figure Figure1)1) [4, 5]. To date, no resistant virus isolate or strain has been identified for which drug resistance against pritelivir or other HPIs was mediated by an amino acid change in UL8. Figure 1. Locations of known resistance DNA mutations in UL5 and UL52 versus mutations identified by DNA sequence analysis of swab specimens from trial participants. These mutations are relative to the consensus. Four different DNA mutations in the region in UL5 ... In a dosage-finding trial in persons with genital HSV type 2 (HSV-2) infection, pritelivir was shown to reduce the level of viral shedding and the recurrence of genital lesions [6]. Here we report the results of a secondary objective of this trial: the monitoring of molecular signals of drug resistance over 28 days of therapy. |
| Databáze: | OpenAIRE |
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