Chemotherapy of Adenovirus Infections (original) (raw)
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Prospects for adenovirus antivirals
2005
Adenoviruses cause a number of self-limiting but often highly infectious diseases that affect multiple organs, most commonly those associated with respiratory, genitourinary and gastrointestinal tracts and the ocular surface. Many factors have driven a search for effective topical and systemic antivirals to adenoviruses. These include patient morbidity, economic losses and chronic visual disturbances associated with epidemic keratoconjunctivitis; and the startling
2022
Purpose: To evaluate the in vitro efficacy of cidofovir, ganciclovir, povidone iodine, chlorhexidine, and cyclosporine A on adenovirus genotype 8 Methods: Conjunctival samples were collected from patients with adenoviral conjunctivitis and cultured in A549 cells. Adenovirus diagnosis was confirmed by RT-PCR. For each drug, the 50% cytotoxic concentration (CC₅₀) was determined. Subsequently, the antiviral activity was tested at concentrations below CC₅₀, and the 50% inhibitor concentration (IC₅₀) of drugs was determined.Results: While the IC₅₀ of cidofovir against adenovirus genotype 8 was 3.07 ± 0.8 µM, ganciclovir, povidone iodine, chlorhexidine, and cyclosporine A were not found to be effective against adenovirus genotype 8 at concentrations below the CC₅₀ value.Conclusions: Cidofovir was found effective and the IC₅₀ value was within the ranges in the literature. Ganciclovir and cyclosporine A were found to be ineffective at doses below the cytotoxic dose, povidone iodine and chlo...
Anti-viral drugs for human adenoviruses
2010
There are many stages in the development of a new drug for viral infection and such processes are even further complicated for adenovirus by the fact that there are at least 51 serotypes, forming six distinct groups (A-F), with different degree of infectivity. This review attempts to address the importance of developing pharmaceuticals for adenovirus and also review recent development in drug discovery for adenovirus, including newer strategies such as microRNA approaches. Different drug screening strategies will also be discussed.
Investigative Ophthalmology & Visual Science, 2006
To determine whether N-chlorotaurine (NCT) demonstrates antiviral activity against adenovirus (Ad) in vitro and in the Ad5/NZW rabbit ocular model. METHODS. The in vitro activity of NCT was evaluated by incubating different Ad serotypes with several concentrations of NCT for 1 hour and determining the reduction in Ad titers. In rabbit study 1, Ad5-infected eyes were treated with 2.5%, 2.0%, and 1.0% NCT; 0.5% cidofovir; or saline. NCT and saline groups were treated 10 times for 1 day and then 5 times daily for 6 days. In rabbit study 2, Ad5-infected eyes were treated with 1.0% NCT/0.1% ammonium chloride (NH 4 Cl), 0.1% NCT/1.0% NH 4 Cl, 0.1% NCT/0.1% NH 4 Cl, and 0.5% cidofovir or saline. The NCT and saline groups were treated five times daily for 10 days. Cidofovir-treated eyes received the authors' standard cidofovir dose regimen: twice daily for 7 days.
The cotton rat model for adenovirus ocular infection: antiviral activity of cidofovir
Antiviral Research, 2004
To determine the antiviral effects of compounds against ocular adenovirus (AdV) infection, we established an animal model of AdV infection in cotton rat eyes. Cotton rat eyes were inoculated intrastromally and topically with four AdV serotypes 4, 5, 8, and 37, and treated topically with 1% HPMPC (cidofovir) eye drops twice a day. The infected corneas were extracted and homogenized, and virus titers in the cornea specimens were determined by a plaque assay. The virus titer in AdV type 5-inoculated eyes peaked on days 0 through 3 after inoculation and virus shedding was detected for 18.0 ± 2.8 days. AdV 5 antigen in the infected corneas was demonstrated in the corneal epithelial cells by immunofluorescence stain. However, for AdV serotypes 4, 8, and 37, no evidence of continued virus replication in cotton rat eyes was noted. Specimens from cidofovir-treated eyes infected with AdV 5 demonstrated a statistically significant reduction in the mean virus titer (days 3-15) (P = 0.028) and virus shedding duration (P = 0.0014), as compared with those of the control group.
Medical Microbiology and Immunology, 2000
Adenovirus (Ad) infection results in signi®cant morbidity and mortality in both immunocompetent and immunosuppressed hosts. There is currently no licensed chemotherapy eective in dealing with this virus infection. In this study the anti-adenoviral activity of a group of modi®ed nucleoside analogs was investigated. The most ecient 3-¯uorosubstituted nucleoside triphosphate inhibitors of Ad DNA polymerase were 3¢uorothymidine triphosphate (IC 50 0.63 lM), 2¢,3¢-dideoxy-3¢-¯uoroguanosine triphosphate (IC 50 0.71 lM) and 2¢,3¢-dideoxy-3¢-¯uorouridine triphosphate (IC 50 2.96 lM). The most ecient 2¢,3¢-dideoxynucleoside triphosphates were 2¢,3¢-dideoxycytidine triphosphate (ddCTP; IC 50 1.0 lM), 2¢,3¢-dideoxyadenosine triphosphate (IC 50 1.6 lM) and 2¢,3¢-dideoxythymidine triphosphate (IC 50 1.82 lM). Kinetic studies indicate competitive inhibition of adenovirus DNA polymerase by ddCTP. These data con®rm results previously obtained at the cellular level using a focus reduction assay involving Ad2-infected FL cells. Whereas the D-enantiomers 3¢-¯uorothymidine and 2¢,3¢-dideoxycytidine are potent inhibitors of adenoviral replication, the corresponding L-enantiomers exhibited no inhibitory activity.
Pharmaceuticals, 2021
Presently, there is no FDA- or EMA-approved antiviral for the treatment of human adenovirus (HAdV) ocular infections. This study determined the antiviral activity of filociclovir (FCV) against ocular HAdV isolates in vitro and in the Ad5/NZW rabbit ocular model. The 50% effective concentrations (EC50) of FCV and cidofovir (CDV) were determined for several ocular HAdV types using standard plaque reduction assays. Rabbits were topically inoculated in both eyes with HAdV5. On day 1, the rabbits were divided into four topical treatment groups: (1) 0.5% FCV 4x/day × 10 d; (2) 0.1% FCV 4x/day × 10 d; (3) 0.5% CDV 2x/day × 7 d; (4) vehicle 4x/day × 10 d. Eyes were cultured for virus on days 0, 1, 3, 4, 5, 7, 9, 11, and 14. The resulting viral eye titers were determined using standard plaque assays. The mean in vitro EC50 for FCV against tested HAdV types ranged from 0.50 to 4.68 µM, whereas those treated with CDV ranged from 0.49 to 30.3 µM. In vivo, compared to vehicle, 0.5% FCV, 0.1% FCV...
Repositioning salicylanilide anthelmintic drugs to treat adenovirus infections
Scientific Reports, 2019
The repositioning of drugs already approved by regulatory agencies for other indications is an emerging alternative for the development of new antimicrobial therapies. The repositioning process involves lower risks and costs than the de novo development of novel antimicrobial drugs. Currently, infections by adenovirus show a steady increment with a high clinical impact in immunosuppressed and immunocompetent patients. The lack of a safe and efficacious drug to treat these infections supports the search for new antiviral drugs. Here we evaluated the anti-adenovirus activity of niclosanide, oxyclozanide, and rafoxanide, three salicylanilide anthelmintic drugs. Also, we carried out the cytotoxicity evaluation and partial characterization of the mechanism of action of these drugs. The salicylanilide anthelmintic drugs showed significant anti-adenovirus activity at low micromolar concentrations with little cytotoxicity. Moreover, our mechanistic assays suggest differences in the way the drugs exert anti-adenovirus activity. Niclosamide and rafoxanide target transport of the HAdV particle from the endosome to the nuclear envelope, whilst oxyclozanide specifically targets adenovirus immediately early gene E1A transcription. Data suggests that the studied salicylanilide anthelmintic drugs could be suitable for further clinical evaluation for the development of new antiviral drugs to treat infections by adenovirus in immunosuppressed patients and in immunocompetent individuals with community-acquired pneumonia. Human adenovirus (HAdV) can be classified into more than 60 serotypes divided into seven species (HAdV-A to-G) 1. The important clinical impact of HAdV infections in immunosuppressed patients is well documented 2-5. Additionally, although the incidence of HAdV in immunocompetent individuals with community-acquired pneumonia (CAP) appears to be low, the current availability of molecular techniques of diagnosis has allowed the identification of HAdV as an important etiologic agent of both occasional cases and outbreaks of CAP in healthy individuals 6-9. Unfortunately, currently there are not approved antiviral drugs to specifically treat HAdV infections and the clinically available broad-spectrum antivirals show no satisfactory therapeutic response in terms of efficacy or safety against HAdV infections 10. The repositioning of drugs already approved by regulatory agencies for other indications is emerging as an alternative for the development of new antimicrobial therapies, a process that involve lower risks and costs than the de novo development of novel antimicrobial drugs 11-13. In this way, niclosamide (NIC), a US Food and Drug Administration (FDA)-approved drug for treating helminthic infections, has previously shown antiviral activity against a broad range of pH-dependent viruses 14-17. NIC was postulated to block virus entry at low micromolar concentrations targeting endosomal acidification. However, a recent publication by Xu et al. suggested that NIC was probably targeting viral replication 14,17. In this study, we evaluated the anti-HAdV activity of NIC and the other two commercially available salicylanilide anthelmintic drugs, oxyclozanide (OXY), and rafoxanide (RAF). All of the drugs examined share a central structure with a core of N-phenyl benzamide (Fig. 1); we examined their activity to evaluate their potential as repositioned drugs to treat HAdV infections.
Anti-Adenovirus Activity of the Medical Intranasal Drug Nazoferon
Mikrobiolohichnyĭ zhurnal, 2021
Currently, 90 different types of human adenoviruses (HAdV) are known, which have been classified into seven species from A to G and new adenovirus types continue to emerge. Antigenic diversity of viruses inhibits the process of creating universal vaccines and causes the development of resistance to direct-acting antiviral drugs. In addition to the rapid development of drug resistance, too narrow a range of existing drugs and a significant number of side effects limits the treatment of adenoviral infections. There is currently no specific etiotropic antiviral drug. Therefore, the development of new effective drugs and the selection of the optimal drug for the treatment of infections caused by adenoviruses remain relevant. The aim of the study was to investigate the antiviral properties of the drugs Nazoferon spray and Nazoferon drops in a model of human adenovirus serotype 3. Methods. Determination of cytotoxicity and antiviral action of drugs was performed by standard colorimetric m...
Pathogenesis and management of adenoviral keratoconjunctivitis
Infection and Drug Resistance, 2018
Human adenovirus (HAdV) is a ubiquitous virus that infects the mucosa of the eye. It is the most common cause of infectious conjunctivitis worldwide, affecting people of all ages and demographics. Pharyngoconjunctival fever (PCF) outbreak is due to HAdV type 3, 4, and 7, whereas outbreaks of epidemic keratoconjunctivitis (EKC) are usually caused by HAdV type 8, 19, 37 and 54. Primary cellular receptors such as coxsackie and adenovirus receptor (CAR), CD46, and sialic acid interact with fiber knob protein to mediate adenoviral attachment to the host cell, whereas adenoviral penton base-integrin interaction mediates internalization of adenovirus. Type 1 immune response to adenoviral ocular infection involves both innate immunity mediated by natural killer (NK) cells and type 1 interferon, as well as adaptive immunity mediated mainly by CD8 T cells. The resulting ocular manifestations are widely variable, with PCF being the most common, manifesting clinically with fever, pharyngitis, and follicular conjunctivitis. EKC, however, is the most severe form, with additional involvement of the cornea, leading to development of subepithelial infiltrates (SEI’s). Because there is currently no US Food and Drug Agency-approved treatment for adenoviral ocular infection, current management is palliative. The presence of sight-threatening complications following ocular adenoviral infection warrants the necessity for developing anti-adenoviral therapy with enhanced therapeutic index. Future trends that focus on adenoviral pathogenesis including adenoviral proteins that utilize host receptors to promote infection could be potential therapeutic targets, yielding a shorter active disease duration and reduced disease burden.