Dataset Information

Synthetic ?-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses.

ABSTRACT: Herpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently determined that certain natural troponoid compounds such as ?-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic ?-hydroxytropolones with the goals of determining a preliminary structure-activity relationship for the ?-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compounds inhibited HSV-1 and HSV-2 replication at 50 ?M, and 10 compounds inhibited HSV-1 and HSV-2 at 5 ?M, with similar inhibition patterns and potencies against both viruses being observed. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concentration (EC50) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC50] of 50 to >100 ?M). Therapeutic indexes ranged from >170 to >1,200. These data indicate that troponoids and specifically ?-hydroxytropolones are a promising lead scaffold for development as anti-HSV drugs provided that toxicity can be further minimized. Troponoid drugs are envisioned to be employed alone or in combination with existing nucleos(t)ide analogs to suppress HSV replication far enough to prevent viral shedding and to limit the development of or treat nucleos(t)ide analog-resistant mutants.

SUBMITTER: Ireland PJ

PROVIDER: S-EPMC4808205 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses.

Ireland Peter J PJ Tavis John E JE D'Erasmo Michael P MP Hirsch Danielle R DR Murelli Ryan P RP Cadiz Mark M MM Patel Bindi S BS Gupta Ankit K AK Edwards Tiffany C TC Korom Maria M Moran Eileen A EA Morrison Lynda A LA

Antimicrobial agents and chemotherapy 20160325 4

Herpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently determined that certain natural troponoid compounds such as β-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic α-hydroxytropolones with the goals of determining a preliminary structu ...[more]

PMID: 26787704

Similar Datasets

Project description:BackgroundHerpes simplex virus (HSV) replication can be detected in the respiratory secretions of a high proportion of ventilated intensive care unit (ICU) patients. However, the clinical significance remains poorly defined. We investigated whether patients with ventilator-associated pneumonia not responding to antibiotics and in whom high levels of HSV could be detected in respiratory secretions benefit from acyclovir treatment.MethodsRespiratory secretions (bronchoalveolar lavage fluid or tracheal aspirates) were tested for HSV replication by quantitative real-time PCR. ICU survival times, clinical parameters, and radiographic findings were retrospectively compared between untreated and acyclovir treated patients with high (> 105 HSV copies/mL) and low (103-105 HSV copies/mL) viral load.ResultsFifty-seven low and 69 high viral load patients were identified. Fewer patients with high viral load responded to antibiotic treatment (12% compared to 40% of low load patients, p = 0.001). Acyclovir improved median ICU survival (8 vs 22 days, p = 0.014) and was associated with a significantly reduced hazard ratio for ICU death (HR = 0.31, 95% CI 0.11-0.92, p = 0.035) in high load patients only. Moreover, circulatory and pulmonary oxygenation function of high load patients improved significantly over the course of acyclovir treatment: mean norepinephrine doses decreased from 0.05 to 0.02 μg/kg body weight/min between days 0 and 6 of treatment (p = 0.049), and median PaO2/FiO2 ratio increased from 187 to 241 between day 3 and day 7 of treatment (p = 0.02). Chest radiographic findings also improved significantly (p < 0.001).ConclusionsIn patients with ventilator-associated pneumonia, antibiotic treatment failure, and high levels of HSV replication, acyclovir treatment was associated with a significantly longer time to death in the ICU and improved circulatory and pulmonary function. This suggests a causative role for HSV in this highly selected group of patients.

Dataset Information

Synthetic ?-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses.

Publications

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets