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At least 37 records · Page 2Linked to original sources
PubMed2000

The evolution of antiviral therapy for external ocular viral infections over twenty-five years.

PURPOSE: To review the past 25 years of the evolution of antiviral therapy for the treatment of common external ocular viral infections (herpes simplex virus type 1, varicella-zoster virus, and adenovirus). METHODS: A broad-based literature review in the fields of virology, antiviral research, and ophthalmology will be carried out. The pathogenesis of the major external ocular viral infections and history of antiviral development will be cited. Important conceptual breakthroughs as well as historical landmarks will be emphasized. RESULTS: The successful development of effective antivirals to treat the most common external ocular viral infections have dramatically reduced morbidity and sight loss. The immune pathogenesis of herpetic stromal keratitis is better understood. CONCLUSIONS: Remarkable progress in the development of antiviral therapy has occurred over the past quarter century. Future needs include improved antivirals and immunomodulators and vaccines to prevent and treat herpetic ocular infections and adenovirus keratoconjunctivitis.

Antiviral Agents↗
PubMed1989

Development of antiviral drugs for the treatment of AIDS: strategies and prospects.

This review makes it clear that there are numerous possibilities for the development of antiviral drugs for the treatment of AIDS. Drug design based on a profound understanding of specific enzymatic regulatory proteins and structural requirements for virus replication is possible. Information regulating these specific processes is increasing rapidly and will further speed preclinical drug design. Over time, this concerted effort to develop anti-AIDS drugs will radically alter the approach to the design of drugs for the treatment of other diseases.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Three-dimensional culture models for human viral diseases and antiviral drug development.

Researchers are recognizing the limitations of two-dimensional (2D) cell cultures, given the fact that they do not reproduce the morphology and biochemical features that the cells possess in the original tissue. As an alternative, the three-dimensional (3D) cell culture approach offers researchers the possibility to study cell growth and differentiation under conditions that more closely resemble the in vivo situation with regard to cell shape and cellular environment. Currently, 3D culture models are being employed in many areas of biomedical research because they offer a more realistic milieu than 2D cultures. The era of 2D culture techniques is moving towards a new epoch of culture systems in 3D. The present review is focused on topics of research on 3D cell cultures in virology and their use in antiviral drug development.

Animals↗
PubMed1986

2',5'-Oligoadenylate synthetase-uninducible alpha/beta-interferon-resistant Friend cells develop an antiviral state when permeabilized with lysolecithin and treated with 2',5'-oligoadenylate oligomers.

Variant sublines of Friend erythroleukemia cells (FLC) that do not respond to alpha/beta-interferon (IFN-alpha/beta) by developing an antiviral state but respond partially to IFN-gamma with an induced antiviral state, lack the ability to induce the 2',5'-oligoadenylate (2-5A) synthetase pathway. Exposure of wild-type and variant cells to exogenous 2-5A oligomers made permeable with lysolecithin resulted in 50-70% inhibition of protein synthesis. Further, the replication of vesicular stomatitis virus in IFN-resistant 2-5A synthetase-deficient FLC exposed to 2-5A trimer was inhibited to the same extent as in wild-type cells. Last, a significant cleavage of ribosomal RNA was observed in samples of total RNAs extracted from variant and wild-type permeabilized FLC, but only if they were exposed to 2-5A. These data are compatible with the conclusion that (i) the activation of the 2-5A-dependent endoribonuclease is not impaired in the variant cells, and (ii) the uninducibility of 2-5A synthetase can be bypassed by exogenously introducing its products, which leads to the establishment of a bona fide antiviral state.

2',5'-Oligoadenylate Synthetase↗
PubMed1979

Effect of nucleosides on interferon production and development of antiviral state induced by poly I.poly C.

Effect of nucleosides both on induction of antiviral state in chick embryo cells (CEC) or rabbit kidney cells (RK13) and on interferon production in RK13 or mouse fibroblast cells (L cells) by polyriboinosinic-polyribocytidylic acid (poly I.poly C) was studied. Addition of inosine or a fifty-fifty mixture of inosine and uridine at a final concentration of 0.1 mM to 10 mM to a growth medium enhanced development of antiviral state in CEC. The nucleoside effect was also observed in RK13 at 0.1 mM but not at a concentration higher than 1 mM. Interferon production in RK13 by superinduction (sequential treatment with metabolic inhibitors after exposure to poly I.poly C) was enhanced 1.5- to 4.0-fold by addition of the nucleoside mixture to the growth medium. When RK13 was pretreated with 10 units per ml of interferon and then superinduced by inhibitors, the enhancing effect of nucleosides on interferon production was not observed. Interferon production in L cells was potentiated a little by addition of 1 mM of the nucleoside mixture to the growth medium. The effect of nucleoside was not observed when the nucleosides were added after exposure to poly I.poly C. The nucleoside effect may be applicable for production of high titered interferon.

Animals↗
PubMedDate not supplied

[Prospects and achievements of genetic engineering in development of antiviral vaccines].

Proceeding from the known data various theoretical and experimental approaches to the construction of gene-engineering vaccines are considered. Gene-engineering subunit vaccines of the first generation are based on isolation of the genes coding for the synthesis of full length capsid proteins with the main antigenic determinants and their subsequent expression in suitable recipient cells. Initial idea of the microbiological synthesis as the main way for production of any antiviral vaccines was not confirmed by the later development. Now for this type of vaccines eucaryotic systems are widely employed using the animal virus vectors and the animal cell cultures. Gene-engineering subunit vaccine of the second generation appears to be a chimeric protein with built-in antigenic determinants of different viruses and maximal immunogenicity in monomeric form. The last point reopens the perspective to use a microbiological synthesis for the production of antiviral vaccines. Besides that the chemically synthesized polypeptide antiviral vaccine will be used widely. In gene-engineering subunit vaccines of the third generation it is possible to use not the natural antigenic determinants which often are characterized by high level of the primary structure changes but artificial (non-natural) antigens, that are the capsid protein conservative regions which under natural conditions of infection or immunization do not induce the protective antiviral antibodies. The recombinant DNA technology in addition to subunit type vaccine allows to construct living vaccines which represent a DNA-containing attenuated virus with build-in natural or synthetic gene of the capsid or chimeric protein with antigenic determinants of another viral species.

Animals↗
PubMed2026

Structural biology of the dengue virus NS2B-NS3 protease as a target for antiviral drug development.

Dengue is the most common global problem in recent times, particularly in tropical and subtropical areas, yet antivirals for therapy or prophylaxis are lacking. Millions of people are affected by this dengue virus, but no proper medication is available yet to cure this disease. One polyprotein that is encoded by the DENV genome is converted into structural and non-structural proteins that are necessary for viral pathogenesis and replication. Among these, the non-structural protein complex NS2B-NS3 is essential for viral polyprotein processing, replication, and host innate immune response control. It acts as a trypsin-like serine protease. The NS2B/NS3 protease is a key enzyme involved in viral replication and serves as a major target for drug development against the dengue virus. The NS3 protease has a conserved catalytic triad (His-Asp-Ser), whereas NS2B serves as an essential cofactor that stabilizes the active conformation of the enzyme and aids in substrate recognition. By disrupting interferon signalling pathways, the NS2B-NS3 protease not only aids in viral replication but also makes immune evasion easier. The compound that inhibits the action of this enzyme could be pioneering in the antiviral drug discovery process. This article provides a comprehensive overview of the detailed structural information of the viral protease (NS2B/NS3) enzyme with the mechanistic role of this enzyme, and highlights various inhibitors related to the NS2B/NS3 protease. A more thorough comprehension of this protease could facilitate the logical development of potent antiviral medications to prevent dengue infection.

Dengue↗
PubMed2006

Prenylation of HDAg and antiviral drug development.

Hepatitis delta virus (HDV) is an important cause of acute and chronic liver disease. Current medical therapies are unable to effectively eradicate HDV infections. Research into the molecular virology of the HDV life cycle has revealed a fascinating collection of biology. These insights are now beginning to be translated into new potential treatment strategies. For example, an essential step in the virus assembly process involves the post-translational lipid modification of a specific HDV protein, namely prenylation of large delta antigen. Preventing prenylation abolishes virus particle formation. Drugs capable of specifically inhibiting prenylation have been developed for use in humans. These agents represent a new class of antiviral agents, with HDV as a first target. Here, a brief review of the HDV life cycle emphasizing the role of prenylation is presented along with implications for drug development and therapy.

Antiviral Agents↗
PubMed2001

Hepatitis C virus cell culture replication systems: their potential use for the development of antiviral therapies.

Hepatitis C virus is a significant public health problem. Current drug regimens have low efficacy against some hepatitis C virus genotypes, while no vaccine is available. The absence of an efficient cell culture system and an accessible small animal model to study hepatitis C virus replication and pathogenesis are major obstacles to the development of effective antiviral therapies. Studies of surrogate model systems, either related viruses or chimeric viruses containing part of the hepatitis C virus genome, have given insight into hepatitis C virus replication, in addition to being a powerful tool for drug discovery. The recent development of an efficient system for the initiation of replication in cell culture provides a viable screen for inhibitors of hepatitis C virus replication. It also brings us much closer to the ultimate goal of an infectious cell culture system for hepatitis C virus.

Antiviral Agents↗
PubMed2005

Potential importance of error catastrophe to the development of antiviral strategies for hantaviruses.

Hantaviruses represent an important and growing source of disease emergence in both established and developing countries. The New World hantaviruses have been touted as potential biological weapons because of their lethality to humans and high infectivity as an aerosol. It is also important to acknowledge the threat that hantaviruses can represent to US troops that operate in a foreign territory endemic for hantavirus infection, as was demonstrated in the Korean War. Effective vaccines, immunotherapeutics and antivirals for the prophylaxis or treatment of hantaviral infections are not available. Recent evidence that hantaviruses are prone to error catastrophe opens the door to the development of new therapeutic strategies. Possible future directions for applying lethal mutagenesis as a strategy for the development of novel and more effective antiviral therapies for treatment of hantavirus infections are discussed.

Animals↗
PubMed1995

Development of antiviral therapy with alpha interferons: promises, false hopes and accomplishments.

This overview describes the development of interferon therapy in four different types of viral diseases. (1) Upper respiratory infections: despite extensive efforts interferons have not found a place in the treatment of these very common diseases. (2) Herpes keratitis: alpha interferons are highly active in combination therapy, but have gained only very limited clinical use. (3) Papillomavirus infections: alpha interferons have been approved for the treatment of papillomavirus infections of skin and mucous membranes and are in fairly wide clinical use. (4) Chronic hepatitis B, C and D: alpha interferons have become the treatment of choice and are used very extensively worldwide. The four examples illustrate both the clinical potentials and the limitations of alpha interferons and give some guidelines for future work. The overall conclusion is that chronic viral diseases lend themselves to interferon therapy more readily than acute viral infections. The general trend is toward the use of interferons in combination therapy.

Hepatitis, Viral, Human↗
PubMed2000

Biochemical and immunologic properties of the nonstructural proteins of the hepatitis C virus: implications for development of antiviral agents and vaccines.

Infection with the hepatitis C virus (HCV) is the major cause of non-A, non-B hepatitis worldwide. The viral genome, a positive-sense, single-stranded, 9.6-kb long RNA molecule, is translated into a single polyprotein of about 3,000 amino acids. The viral polyprotein is proteoytically processed to yield all the mature viral gene products. The genomic order of HCV has been determined to be C-->E1-->E2-->p7-->NS2-->NS3-->NS4A-->NS4B-->NS5A++ +-->NS5B. C, E1, and E2 are the virion structural proteins. Whereas the function of p7 is currently unknown, NS2 to NS5B are thought to be the nonstructural proteins. Generation of the mature nonstructural proteins relies on the activity of viral proteinases. Cleavage at the NS2-NS3 junction is accomplished by a metal-dependent autocatalytic proteinase encoded within NS2 and the N-terminus of NS3. The remaining downstream cleavages are effected by a serine proteinase contained also within the N-terminal region of NS3. NS3, in addition, contains an RNA helicase domain at its C-terminus. NS3 forms a heterodimeric complex with NS4A. The latter is a membrane protein that acts as a cofactor of the proteinase. Although no function has yet been attributed to NS4B, NS5A has been recently suggested to be involved in mediating the resistance of the HCV to the action of interferon. Finally, the NS5B protein has been shown to be the viral RNA-dependent RNA polymerase. This article reviews the current understanding of the structure and the function of the various HCV nonstructural proteins with particular emphasis on their potential as targets for the development of novel antiviral agents and vaccines.

Antiviral Agents↗
PubMed1992

Development of antiviral treatment strategies in murine models.

Murine models with type C murine leukemia viruses have been used to develop major new prophylactic and therapeutic strategies in vaccination, drug therapy of acute virus exposure and chronic viremia, combination therapy, prevention of maternal transmission, and therapy targeted to the central nervous system. Transgenic mice expressing either the whole human immunodeficiency virus type 1 (HIV-1) provirus or subgenomic sequences allow the in vivo analysis of selected HIV-1 functions. The full replicative cycle of HIV-1 can be studied in human/mouse chimerae which were created by transplanting human hematolymphoid cells into SCID mice. The chimeric SCID mouse models have been used successfully to evaluate anti-HIV-1 drugs. The role of the various murine retrovirus systems in the development of anti-HIV-1 and anti-AIDS therapies is summarized.

Animals↗
PubMed2006

Smallpox antiviral drug development: satisfying the animal efficacy rule.

Concerns over the potential use of variola virus as a biological weapon have prompted new interest in the development of small molecule therapeutics to prevent and treat smallpox infection. Since smallpox is no longer endemic, human clinical trials designed to link antiviral efficacy to clinical outcome have been supplanted by antiviral efficacy evaluations in animal models of orthopoxvirus disease. This poses a unique challenge for drug development; how can animal efficacy data with a surrogate virus be used to establish clinical correlates predictive of human disease outcome? This review will examine the properties of selected animal models that are being used to evaluate poxvirus antiviral drug candidates, and discuss how data from these models can be used to link drug efficacy to clinical correlates of human disease.

Animals↗
PubMed1998

The identification and development of antiviral agents for the treatment of chronic hepatitis B virus infection.

Hepatitis B virus (HBV) is the leading cause of chronic hepatitis throughout the world. Notwithstanding the availability of a safe and effective vaccine, the world prevalence of HBV has not declined significantly, thus resulting in the need for a selective antiviral agent. HBV is a small, partially double-stranded DNA virus which replicates through an RNA intermediate. Most efforts to develop anti-HBV agents have been targeted to the viral DNA polymerase which possesses reverse transcriptase activity. Currently, the most promising anti-HBV agents are nucleoside analogs which interfere with viral DNA replication. Although earlier nucleoside analogs such as vidarabine (ara-A) and fialuridine (FIAU) have displayed unacceptable toxicities, newer analogs such as lamivudine (3TC), bis-POM PMEA (GS-840), lobucavir, and BMS-200,475 have demonstrated clinical utility. In particular, the use of lamivudine has generated considerable interest in the development of other L-enantiomeric nucleoside analogs for use against HBV. Here, we provide an overview of HBV structure and replication strategy and discuss the use of cell culture systems, in vitro viral polymerase systems, and animal models to identify and evaluate anti-HBV agents. We also discuss the various classes of nucleoside analogs in terms of structure, mechanism of action, status in clinical development, ability to select for resistant HBV variants, and use in combination therapies. Finally, we present a discussion of novel antiviral approaches, including antisense and gene therapy, and address the various challenges to successful anti-HBV chemotherapeutic intervention.

Animals↗