The face of future hepatitis C antiviral drug development: recent biological and virologic advances and their translation to drug development and clinical practice.
Explore the source record for details and available documents.
Animals↗
SEARCH · Search PubMed
Results for “antiviral development”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Antiviral prodrugs - the development of successful prodrug strategies for antiviral chemotherapy.
Following the discovery of the first effective antiviral compound (idoxuridine) in 1959, nucleoside analogues, especially acyclovir (ACV) for the treatment of herpesvirus infections, have dominated antiviral therapy for several decades. However, ACV and similar acyclic nucleosides suffer from low aqueous solubility and low bioavailability following oral administration. Derivatives of acyclic nucleosides, typically esters, were developed to overcome this problem and valaciclovir, the valine ester of ACV, was among the first of a new series of compounds that were readily metabolized upon oral administration to produce the antiviral nucleoside in vivo, thus increasing the bioavailility by several fold. Concurrently, famciclovir was developed as an oral formulation of penciclovir. These antiviral 'prodrugs' thus established a principle that has led to many successful drugs including both nucleoside and nucleotide analogues for the control of several virus infections, notably those caused by herpes-, retro- and hepatitisviruses. This review will chart the origins and development of the most important of the antiviral prodrugs to date.
Animals↗
Development of antiviral therapy for severe acute respiratory syndrome.
A new disease, the severe acute respiratory distress syndrome (SARS), caused by the SARS coronavirus (SARS-CoV), emerged at the beginning of 2003 and rapidly spread throughout the world. Although the disease had disappeared in June 2003 its re-emergence cannot be excluded. The development of vaccines against SARS-CoV may take years. Therefore, the availability of effective antiviral drugs against SARS-CoV may be crucial for the control of future SARS outbreaks. In this review, experimental and clinical data about potential anti-SARS drugs is summarised and discussed. Animal model studies will be needed to help to determine which interventions warrant controlled clinical testing.
Animals↗
Orthopoxvirus targets for the development of antiviral therapies.
The potential use of smallpox virus as a bioterror agent and the endemic presence of monkeypox virus in Africa underscores the need for better therapies for orthopoxvirus infections. The only existing clinical experience treating vaccinia and smallpox infections has been with Marboran, which suggested that antiviral therapies could be effective in treating and preventing smallpox infections, but this compound has not been pursued. Drugs that have been approved for other indications, like cidofovir, could be approved for the treatment of orthopoxvirus infections in a timely manner, and this compound has already been approved for emergency treatment of smallpox and complications from vaccination. Its lack of activity when given orally, however, limits its use in a major outbreak involving large numbers of people exposed to the virus. The discovery and development of new therapies can be achieved more rapidly by drawing on the experience and successes with other antiviral agents, particularly with the herpesviruses. This review will discuss the orthopoxvirus replication cycle in detail noting specific viral functions and their associated gene products that have the potential to serve as new targets for drug design and development. This discussion is designed to help investigators relate these targets to parallel functions and existing assays in other virus systems that have been used successfully in drug development. The rapid progress that has been achieved in recent years should yield new drugs for the treatment of these infections and might also reveal new strategies for antiviral therapy with other viruses.
Animals↗
Development of antiviral levels of ribavirin in serum and urine of orally treated rats.
The levels of ribavirin or its antivirally active metabolic products were determined in the serum and urine of rats treated with single oral doses of 1,000 or 100 mg/kg of the compound, using a newly developed micromethod in which measles virus inhibition was assayed in BS-C-1 cells. At the high dosage level, maximum ribavirin serum levels of 24 microgram/ml were observed 2 h postribavirin administration. Approximately 10-fold less active material was seen in the rats receiving the lower ribavirin dosage; this peak effect was seen 1 h after treatment. Urine excretion was maximal between 4 and 20 h after treatment in both dosage groups.
Administration, Oral↗
Antivirals at the mirror: the lack of stereospecificity of some viral and human enzymes offers novel opportunities in antiviral drug development.
The enantioselectivity of enzymes, namely the property of enzymes to recognise and metabolise only one of the two enantiomers of chiral molecules, is related to the chiral structure of the enzymes, reflecting the three-dimensional folding of the polypeptide backbone and the orientation of the amino acid side chains in the folded molecule. Because of the chirality of the amino acids (L), the chemistry of life should be highly sensitive to different enantiomers of chiral substrates. However, in a world consisting only of D-nucleosides and L-amino acids, an enzyme which lacks enantio-selectivity does not reduce its fitness, since there is no chance of molecular misunderstanding when no other choice is available. Thus, although enantioselectivity is theoretically essential for life we do not expect to be always present among the biochemical properties of enzymes. If this is the case for key enzymes involved in virus infection or cancer, how to exploit such lack of enantioselectivity for a novel approach to antiviral or anticancer chemotherapy? The present review will discuss the possible lack of enantioselectivity of enzymes and its relevance for the developing of novel drugs with the inverted optical configuration.
Antiviral Agents↗
Recent developments in antiviral chemotherapy.
As can be seen from the preceding brief discussion, the prospects for new antiviral agents for the treatment of viral diseases ranging in severity from the common cold to AIDS appear promising. The latest advances in technologies such as crystallography, genetic engineering, and monoclonal antibodies are all being applied to the discovery of new ways to inhibit virus-specific processes. In addition, the development of diagnostic tests for viral diseases has proceeded at a rapid pace that should facilitate the proper use of the antivirals when they become available. The one lesson that has been learned in the antiviral field over the past decade is that virus-specific inhibitors do exist, and if an essential virus-specific process or protein can be identified, it is likely that a molecule can be found to inhibit or inactivate it.
Antiviral Agents↗
Interferon binding: the first step in establishment of antiviral activity.
Chick cells incubated at 1 degrees C with interferon fail to develop antiviral activity, but this activity appears subsequent to a 7-hour incubation at 37 degrees C after removal of interferon by repeated washings. Treatment with actinomycin D blocks the development of the latter activity. Cells incubated with interferon at 1 degrees C for up to 1 hour and then washed and incubated for 2 hours at 37 degrees C develop a degree of antiviral activity proportional to the concentration of interferon at initial incubation; at any concentration, the antiviral activity increased with the duration of initial incubation at 1 degrees C, but a maximal response was reached at 10 or 20 minutes. Treatment with trypsin after incubation with interferon at 1 degrees C inhibited development of antiviral activity. Interferon is rapidly bound to a superficial cell site, and this binding is necessary for development of antiviral activity in chick cells.
Animals↗
Interferon system of human cornea cells: interferon production, characterization, and development of antiviral state.
The interferon (IFN) system of human cornea cells in culture was studied. IFN produced by these cells by infection with Newcastle disease virus (NDV) was shown, by neutralization studies with specific antisera against human alpha interferon (HuIFN-alpha) and human beta interferon (HuIFN-beta), to contain 90-95% antiviral activity characteristic of the HuIFN-beta and 5-10% that of HuIFN-alpha. The chromatographic behavior of human cornea IFN on Con A-Sepharose and zinc chelate agarose columns was identical to that of HuIFN-beta produced by human foreskin cells. The cornea cells developed marked resistance when exposed to either HuIFN-beta or human gamma interferon (HuIFN-gamma) against vesicular stomatitis virus (VSV), but to a much lesser degree against HSV-1. Both the laboratory-adapted strain and a clinical isolate of HSV-1 were found to be resistant to HuIFN-beta and HuIFN-gamma as compared with VSV. The clinical isolate of HSV-1 was, however, more sensitive to HuIFN-gamma than the laboratory-adapted strain. Furthermore, a combination of HuIFN-beta and HuIFN-gamma did not significantly increase the level of antiviral state induced in cornea cells against HSV-1. These results suggest that in-vitro culture of human cornea cells can be a valuable system to evaluate the potential of chemotherapeutic agents against common ophthalmic viral infections.
Cells, Cultured↗
Development of antiviral agents for the treatment of human immunodeficiency virus infection.
Antiviral agents under investigation for the treatment of patients infected with the human immunodeficiency virus (HIV) are reviewed. Multiple mechanisms exist by which antiviral agents might inhibit the replication of HIV or eradicate its latent form in affected cells, or both. These mechanisms include (1) interference with the cell surface receptor for HIV, (2) prevention of uncoating of viral particles, (3) inhibition of reverse transcriptase, (4) prevention of integration and posttranscription processing, (5) interference with viral assembly, and (6) interference with virus release. Most agents developed thus far work by inhibiting HIV reverse transcriptase. Suramin, ribavirin, ammonium 21-tungsten-9-antimoniate (HPA-23), foscarnet (phosphonoformate, PFA), inosine pranobex (isoprinosine), peptide T, ampligen, AL 721, dideoxycytidine, and zidovudine (formerly azidothymidine) have antiretroviral activity in vitro. To date zidovudine is the only antiretroviral agent approved by the FDA as clinically effective. However, zidovudine has serious toxicities, including neutropenia and anemia; in some patients dosage reduction or cessation of therapy may be necessary. Because treatment with zidovudine does not cure HIV infection, numerous studies are under way with other anti-HIV agents. Ultimately, combinations of agents probably will be used to suppress or eradicate HIV. While the search for more efficacious and less toxic treatments continues, the development of zidovudine in such a short time provides hope that progress toward a cure will be made rapidly.
Acquired Immunodeficiency Syndrome↗
Antiviral drug development for the treatment of human immunodeficiency virus infections. An overview.
During 1987, a new era in the approach to treatment of severe human immunodeficiency virus (HIV)-I infections was entered. The increased availability of zidovudine and its licensure in many countries have resulted in its widespread use. With these developments have come a multitude of new questions. How long will clinical benefit be sustained? Will zidovudine be useful in asymptomatic HIV carriers and in other HIV-related conditions? How can the diversion of zidovudine to unproven indications be averted so that properly controlled clinical trials are conducted? Can better treatment regimens be developed to enhance the therapeutic/toxic ratio of zidovudine? What are the proper roles of governments in assuring patient access to zidovudine? How should newer anti-HIV drugs be compared with zidovudine? Will combinations of zidovudine and other active agents be useful? To address many of these issues in the United States, the Federal Government has established an AIDS Clinical Trials Group (ACTG) program. Over 3,000 patients have been enrolled in AIDS Clinical Trials Group trials, which span the spectrum from asymptomatic to advanced HIV-I infections. In addition, drug development and screening programs have been established to evaluate new compounds and regimens. Although control of AIDS will be a long and arduous journey, an important beginning has been made.
Acquired Immunodeficiency Syndrome↗
The 4',4'-difluoro analog of 5'-noraristeromycin: a new structural prototype for possible antiviral drug development toward orthopoxvirus and cytomegalovirus.
As a surrogate for 4'-hydroxy-5'-noraristeromycin and related carbocyclic nucleosides, an efficient, enantiodivergent synthetic route to both enantiomers of 5-(6-amino-9H-purin-9-yl)-3,3-difluorocyclopentane-1,2-diol (6 and ent-6) has been developed from a common starting material ((+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate, 10). Both compounds were assayed versus a series of viruses. The only response found was for compound 6 toward vaccinia and cowpox (EC50 of 143 and 94 microM, respectively) and human cytomegalovirus (EC50 of 6.2 microM). Both compounds were non-cytotoxic. While not as active as cidofovir toward the orthopox viruses and ganciclovir toward cytomegalovirus, compound 6 offers a new structural prototype upon which to build for uncovering new agents effective against these viral types.
Adenosine↗
Development of antiviral therapy for chronic infection with hepatitis B virus.
Explore the source record for details and available documents.
Antiviral Agents↗
Can ethnopharmacology contribute to the development of antiviral drugs?
In recent years, many compounds having potent antiviral activity in cell cultures and in experimental animals have been detected, but only a few have been approved by Western health authorities for clinical use. Nevertheless, some of these compounds are currently undergoing either preclinical or clinical evaluation, and perspectives for finding new interesting antiviral drugs are promising. Among these antiviral substances are several natural compounds isolated from plants used in traditional medicine including polysaccharides, flavonoids, terpenes, alkaloids, phenolics and amino acids. Some of these plant compounds exhibit a unique antiviral mechanism of action and are good candidates for further clinical research. What follows is a brief summary of the selection methods of plants for antiviral screening and in vitro and in vivo assays, which are currently used for detecting this activity in plant extracts. The importance of the plant kingdom as a source of new antiviral substances will be illustrated by presenting a survey on plant-derived antirhinovirus and anti-HIV agents.
Animals↗
Recent trends and development in antiviral chemotherapy.
Explore the source record for details and available documents.
Acyclovir↗
Surrogacy in antiviral drug development.
The coming of age of molecular biology has resulted in an explosion in our understanding of the pathogenesis of virus related diseases. New pathogens have been identified and characterized as being responsible for old diseases. Empirical clinical evaluation of morbidity and mortality as outcome measures after a therapeutic intervention have started to give way to the use of an increasing number of surrogate markers. Using a combination of these markers, it is now possible to measure and monitor the pathogen as well as the host's response. Nowhere is this better exemplified in virology than in the field of AIDS. We have utilized the advances in pathogenesis and new antiretroviral drug development to: * develop a new class of drugs which block the entry of HIV-1 into cells. * develop a new approach for effectively delivering these drugs to those tissues in which most viral replication takes place. Over the last 10 years, our work has progressed from concept to clinical trial. Our laboratory based evaluation of the new molecules developed as well as our clinical evaluation of their safety and efficacy have had to respond and adapt to the rapid changes taking place in AIDS research. This paper discusses the problems encountered and the lessons learnt.
Antiretroviral Therapy, Highly Active↗
Experiences in developing potential antiviral compounds.
Explore the source record for details and available documents.
Animals↗
A rational approach to the development of antiviral chemotherapy: alternative substrates of herpes simplex virus Type 1 (HSV-1) and Type 2 (HSV-2) thymidine kinase (TK).
Explore the source record for details and available documents.
Antiviral Agents↗