Prospects for adenovirus antivirals (original) (raw)
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Chemotherapy of Adenovirus Infections
Adenoviruses [Working Title]
Adenoviruses occupy a substantial place as causative agents of seasonal respiratory infections, the most characteristic and severe being epidemic keratoconjunctivitis (EKC). Moreover, adenovirus infections are very characteristic with their severe course in persons with impaired immune system. The absence of specific anti-adenovirals is the major problem, and the development of compounds effective against adenoviruses is a principal task. This chapter embraces the results of studies on search for antivirals with anti-adenovirus activity, nucleoside/nucleotide analogues and nonnucleoside compounds. Ganciclovir and cidofovir demonstrated effects against adenovirus serotypes in vitro and in animal ocular infection models. Cidofovir applied alone or in combination with cyclosporine manifested therapeutic effects on patients with EKC in a controlled clinical study. We characterized abitylguanide as anti-adenovirus agent in broad-scale investigations, including cell culture experiments, and in two double-blind trials with very beneficial results.
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.
Adenovirus and the Cornea: More Than Meets the Eye
Viruses, 2021
Human adenoviruses cause disease at multiple mucosal sites, including the respiratory, gastrointestinal, and genitourinary tracts, and are common agents of conjunctivitis. One site of infection that has received sparse attention is the cornea, a transparent tissue and the window of the eye. While most adenovirus infections are self-limited, corneal inflammation (keratitis) due to adenovirus can persist or recur for months to years after infection, leading to reduced vision, discomfort, and light sensitivity. Topical corticosteroids effectively suppress late adenovirus keratitis but are associated with vision-threatening side effects. In this short review, we summarize current knowledge on infection of the cornea by adenoviruses, including corneal epithelial cell receptors and determinants of corneal tropism. We briefly discuss mechanisms of stromal keratitis due to adenovirus infection, and review an emerging therapy to mitigate adenovirus corneal infections based on evolving knowle...
Targeting species D adenoviruses replication to counteract the epidemic keratoconjunctivitis
Biochimie, 2015
Human adenoviruses are non-enveloped DNA viruses causing various infections; their pathogenicity varies dependent on virus species and type. Although acute infections can sometimes take severe courses, they are rarely fatal in immune-competent individuals. Adenoviral conjunctivitis and epidemic keratoconjunctivitis are hyperacute and highly contagious infections of the eye caused by human adenovirus types within species D. Currently there is no causal treatment available to counteract these diseases effectively. The E2B region of the adenovirus genome encodes for the viral DNA polymerase, which is required for adenoviral DNA replication. Here we propose novel model systems to test this viral key factor, DNA polymerase, as a putative target for the development of efficient antiviral therapy based on RNA interference. Using our model cell lines we found that different small interfering RNAs mediate significant suppression (up to 90%) of expression levels of viral DNA polymerase upon t...
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.
Management of Adenoviral Keratoconjunctivitis: Challenges and Solutions
Clinical Ophthalmology, 2020
Human adenovirus (HAdV) is the most common cause of infectious conjunctivitis, accounting for up to 75% of all conjunctivitis cases and affecting people of all ages and demographics. In addition to ocular complications, it can cause systemic infections in the form of gastroenteritis, respiratory disease, and dissemination in immunocompromised individuals. HAdV causes lytic infection of the mucoepithelial cells of the conjunctiva and cornea, as well as latent infection of lymphoid and adenoid cells. Epidemic keratoconjunctivitis (EKC) is the most severe ocular manifestation of HAdV infection, in which the presence of subepithelial infiltrates (SEIs) in the cornea is a hallmark feature of corneal involvement. SEIs have the tendency to recur and may lead to long-term visual disability. HAdV persistence and dissemination are linked to sporadic outbreaks of adenoviral keratoconjunctivitis. There is no FDA-approved antiviral for treating adenoviral keratoconjunctivitis, and as such, solutions should be proffered to handle the challenges associated with viral persistence and dissemination. Several treatment modalities have been investigated, both systemically and locally, to not only mitigate symptoms but reduce the course of the infection and prevent the risk of long-term complications. These options include systemic and topical antivirals, in-office povidone-iodine irrigation (PVI), immunoglobulin-based therapy, antiinflammatory therapy, and immunotherapy. More recently, combination PVI/dexamethasone ophthalmic formulations have shown favorable outcomes and were well tolerated in clinical trials for the treatment of EKC. Possible, future treatment considerations include sialic acid analogs, cold atmospheric plasma, N-chlorotaurine, and benzalkonium chloride. Continued investigation and evaluation of treatment are warranted to reduce the economic burden and potential long-term visual debilitation in affected patients. This review will focus on how persistence and dissemination of HAdV pose a significant challenge to the management of adenoviral keratoconjunctivitis. Furthermore, current and future trends in prophylactic and therapeutic modalities for adenoviral keratoconjunctivitis will be discussed.
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...
PREVENTION OF ADENOVIRAL EYE INFECTION — REVIEW
Epidemic viral conjunctivitis caused by adenovirus is the most common infectious conjunctivitis. The exact incidence of adenoviral conjunctivitis is still poorly known, but there are two well-defined ade-noviral keratoconjunctivitis clinical syndromes: epidemic keratoconjunctivitis (EKC) and pharyngoconjun-ctival fever (PCF). Epidemic keratoconjunctivitis is also the most severe form and presents with watery discharge , hyperemia, chemosis and ipsilateral lympha-denopathy. Diagnosis is mainly clinical, but its etiol-ogy can be confirmed using cell cultures, antigen detection , polymerase chain reaction or immune-chromatography. Multiple treatments have been tried for this disease, but none of them seem to be completely effective. Viruses are resistant to desiccation and certain common surface disinfectants. Prevention is the most reliable and recommended strategy to control this epidemic infection. Global epidemic surveillance system definitely needs to be established to monitor and analyze the epidemic conjunctivitis in the future. There is clearly a need for the national and the military public health institutions to work together on guidelines to handle future challenges.
Adenoviruses – Infection, pathogenesis and therapy
FEBS Letters, 2020
Both well-known and emerging viruses increasingly affect humans and cause disease, sometimes with devastating impact on society. The viruses present in the biosphere are the top predators in the life chain, virtually without enemies, except perhaps the immune system, and harsh environmental physicochemical conditions restricting their dissemination. We know a lot about viruses, but do we know enough? This series of reviews is dedicated to adenoviruses (AdVs), a family of nonenveloped DNA viruses occurring in vertebrates, including humans. AdVs have been the focus of intense research for more than 67 years. Besides causing disease, they have immensely contributed to the advance of life sciences and medicine over the past decades. Recently, AdVs have been widely used as vehicles in gene therapy and vaccination. They continue to provide fundamental insights into virus-host interactions in cells, tissues and organisms, as well as systems and metabolic networks. This special issue of FEBS Letters presents a unique collection of 23 state-of-the-art review articles by leading adenovirologists. In this prelude, I present the chapters, which provide a solid basis for further exploring the rich heritage in adenovirus molecular cell biology, structural biology, genetics, immunology, gene therapy and epidemiology. I conclude with an essential discussion of six blind spots in adenovirology.