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Category: Viruses and Viral Pathogenesis; Clinical Microbiology
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This book captures the state of the science with twenty reviews that examine the latest in today’s antiviral drug discovery efforts. The introduction of nucleoside analogs and investigations of novel antiviral targets have brought significant new possibilities to the field. These reviews range from in-depth analyses of a specific viral target, to examination of multiple targets in medically important viruses. All chapters include the authors’ thoughts regarding future developments in their specific topic, and the book concludes with an Afterword in which several experts consider the general future of antiviral drug discovery.
With its coverage of many different types of viruses including influenza virus, herpesvirus, the SARS coronavirus, orthopox- and flaviviruses, hepatitis C virus, and a wide range of topics in HIV-1, Antiviral Research offers investigators a broad view of the current state of nucleoside analogs and other antiviral strategies. This book is certain to help stimulate new ideas and approaches for virologists, biochemists, pharmaceutical chemists, and other investigators.
Electronic Only, 373 pages, full-color insert, illustrations, index.
Acyclovir (ACV), whose mechanism is detailed in this chapter, heralded the second generation of antivirals for herpesviruses and set the standard for the development of antiviral drugs. Two limitations of oral acyclovir have been its limited oral bioavailability (~15%) and short half-life. These limitations require administration of large pills as often as every four hour. Valacyclovir and famciclovir overcome these limitations and would have completely displaced the use of acyclovir except for the expiration of the acyclovir patent resulting in the availability of low-cost generic drug. Both valacyclovir and famciclovir can be used for applications of oral acyclovir. In the herpesviruses considered here, there are six gene products with activities at the replication fork. The viral proteins that have thus far served as the best targets for antiherpesvirus drugs are the viral DNA polymerases that are required for viral DNA replication, which are thus targets for inhibition, and viral kinases. All of the nucleoside analogs discussed in this chapter are converted to analogs of deoxynucleoside triphosphates (dNTPs) that inhibit herpesvirus DNA polymerases. The mechanism of acyclovir action begins with the TK encoded by herpes simplex virus (HSV) or varicella-zoster virus (VZV). An important unanswered question is whether new antiherpesvirus drugs can be developed to combat drug-resistant human infections. Although the number of drug-resistant HSV infections is relatively small, the need for new drugs that are active against acyclovir-resistant viruses and that have good pharmacokinetic and toxicity profiles is substantial for the patients involved.
Highly active antiretroviral therapy (HAART) based on the combination of different classes of inhibitors has dramatically improved the prognosis of human immunodeficiency virus type 1 (HIV-1) infection after its establishment. This chapter focuses on the viral entry processes that play crucial roles in HIV-1 replication and describes inhibitors thereof. It talks about three kinds of inhibitor named as fusion inhibitors, coreceptor inhibitors and viral attachment inhibitors. Maraviroc was approved for use in combination with other antiretroviral medications for the treatment of R5 HIV-1 in adults whose viral loads remain detectable despite existing antiretroviral treatment or who have multidrug-resistant HIV-1. HIV-1 variants resistant to Cyanovirin-N (CV-N) or cross-resistant to additional carbohydrate-binding agents were generated and examined for their biological properties. A study on resistance to CV-N demonstrated that the resistant variants had increased susceptibility to immunoglobulins and sera obtained from HIV-1-infected patients and particularly to V3-loop-directed monoclonal antibodies. The maraviroc-resistant R5 HIV-1 retained full susceptibility to SCH-C and aplaviroc, suggesting that although the CCR5 binding sites for these agents are similar, their impacts on the surface conformation of the receptor are different. The results of the study also suggest that the envelope proteins of maraviroc-resistant viruses are able to recognize and utilize inhibitor-bound CCR5, which involves the ordered accumulation of mutations in the viral envelope, both in the V3 loop and elsewhere within gp120. In addition to the inhibitors described in the chapter, several antibodies have been shown to interact with the molecules essential for HIV-1 entry to the host cells.
This chapter discusses the non-nucleoside reverse transcriptase inhibitors (NNRTI), which is a valuable component of first-line highly active antiretroviral therapy (HAART) today. Reverse transcriptase (RT) is an essential enzyme in the replication cycle of HIV. Several high-resolution structures representing the different intermediates in the polymerization reaction are available for human immunodeficiency virus type 1 (HIV-1) RT. Rilpivirine is currently in phase IIb clinical trials for treatment of HIV-1 infection in treatment-naïve subjects. With the widespread use of anti-HIV therapy, resistance has grown steadily and is now common among treatment-experienced HIV-infected patients, with NNRTI resistance occurring in 20 to 30% of patients. This has changed with the DUET-1 and DUET-2 trials, two large phase III clinical trials that examined the efficacy of etravirine in treatment-resistant HIV-1-infected patients. K103N and Y181C were the first NNRTI mutations to be identified and to date are among the most prevalent in clinical HIV-1 isolates. They have been observed in patients failing on nevirapine, efavirenz, or delavirdine, and the clinical utility of these drugs is hampered by the presence of a single K103N or Y181C mutation. Recently, predictors of virologic response to etravirine were identified based on pooled data from DUET-1 and DUET-2.
More than 20 different antiretroviral agents have been approved for human immunodeficiency virus (HIV) treatment. These compounds target distinct stages in the life cycle of this retrovirus that include (i) its entry into the cytoplasm, which marks the beginning of the infection; (ii) the process of reverse transcription, i.e., the conversion of the single-stranded RNA genome into double-stranded DNA; (iii) the integration of proviral, double-stranded DNA into the host chromosome; and (iv) the processing of viral precursor proteins at later stages. These steps are vital for viral replication, and with the exception of the entry process, each of the aforementioned reactions involves viral enzymes, i.e., the reverse transcriptase (RT), the integrase, and the protease, respectively, that can be targeted by antiretroviral drugs. This chapter focuses on nucleoside analogue RT inhibitors (NRTIs) in the context of mechanisms of action and resistance and on the implications for the development of future strategies designed to counteract resistance. All approved NRTIs show a broad spectrum of antiviral activity against HIV-1, HIV- 2, and sometimes even hepatitis B virus (HBV), which points to structurally highly related active sites. A given mutation or mutational cluster can affect susceptibility to different NRTIs to various degrees, which makes it difficult to group the mutations. It will be interesting to investigate how established and novel NRTIs can be most effectively combined with new classes of compounds with the ultimate goal of further reducing the risk of resistance development, while maintaining high standards regarding problems associated with toxicities and dosing.
This chapter describes the unique role of integrase (IN) in the human immunodeficiency virus type 1 (HIV-1) replication cycle and its interaction with different cellular proteins. It addresses the efficacy and toxicity data of the new drugs targeting IN, along with their biochemical, pharmacokinetic, and pharmacodynamic characteristics. It also discusses clinical perspectives and viral resistance against IN inhibitors as well as recently identified new antiviral targets in HIV IN. Since retroviral integration is a multistep process, the different cofactors can theoretically play a role during one of the following steps: (i) catalysis, (ii) nuclear import of the PIC, (iii) target site selection, and (iv) repair of the DNA gaps. The chapter gives an overview of the search for HIV-1 IN inhibitors, and discusses current IN inhibitors in clinical development. The major mechanism of clearance of MK-0518 (raltegravir) in humans is UDP-glucuronyltransferase (UGT) isoform, 1A1-mediated glucuronidation. In a multicenter, double-blind, randomized study (MK-0518 protocol 005), the safety and efficacy of MK-0518 versus placebo, both regimens also using optimized background therapy (OBT), were evaluated. This study was designed to include highly antiretroviral therapy (ART)-experienced patients with a documented genotypic/phenotypic resistance for more than one drug in each of the three classes (NNRTI, NRTI, and PI) with HIV RNA levels of >5,000 copies and CD4 counts of >50 cells/mm3. Resistance to IN inhibitors has been relatively well defined for a new class of antiretroviral agents. IN has only been recently validated in clinical trials as a target for antiretroviral therapy.
This chapter discusses the potential of HIV Tat, Rev, and their cellular cofactors as drug targets. Tat interacts with numerous transcriptional regulatory factors and presumably by virtue of its interaction with transcription activation response (TAR) RNA, recruits these factors to the human immunodeficiency virus type 1 (HIV-1) promoter. Thus, HIV-1 transcription directed from the viral long terminal repeat (LTR) is balanced by the actions of kinases and phosphatases, and both can be potential targets for drug development. Tat promotes the elongation of viral transcripts by increasing the occupancy time of CDK9/cyclin T1 on the HIV-1 LTR. Small-molecule inhibitors of Tat-TAR RNA interaction, small-molecule inhibitors of CDKs such as CDK9 or CDK2, and inhibitors that disrupt the interaction of Tat with additional host cell factors such as p300/CREB binding protein-associated factor (PCAF) and/or inhibit cellular activities of the host cell factors could all be viable anti-HIV drug candidates. Both Tat and TAR RNA are essential for activated HIV-1 transcription, and were thus the first candidates to be considered for drug design that targeted HIV-1 transcription. Antiviral development against HIV-1 regulatory proteins Tat and Rev represents a conceptual work in progress. In the arena of inhibiting Tat and Rev cellular cofactors, the concerns over host toxicity have not been fully resolved. Future efforts are needed to address the two major challenges of mechanistic specificity and functional toxicity.
HIV protease inhibitors (PIs) were first introduced into clinical practice in 1996, and their use has resulted in major clinical benefits for human immunodeficiency virus (HIV) -infected people in terms of better viral suppression, improved immune restoration, reduced morbidity, and longer survival. This chapter focuses on the biochemical and molecular basis of inhibition of HIV-1 aspartic protease (PR), the virological basis of PI resistance, and implications on the therapeutics of HIV infections and proposes the research that is still needed in order to further improve on the benefits that PIs offer for HIV medicine. Drug-resistant viruses have been described for all PIs developed to date. Some strains of HIV recovered from extensively treated patients display cross-resistance to a variety of PIs. Additionally, structural data from a highly resistant PR containing 10 resistance mutations revealed an expansion in the active site, as a result of a separation of the flaps by as much as 10 Å, while this distance is only 4 Å in the case of wild-type PR. The degree of suppression of viral replication is the result of the interaction between exposure of the virus to the drug and the inherent susceptibility of the infecting virus to such drug, all this within the diverse environments of human tissues. The study of efflux transporters and their role in PI penetration into, and distribution within, so-called sanctuary sites may lead to ways of making HIV in these compartments more susceptible to antiretrovirals (ARVs).
This chapter focuses on Hepatitis C virus (HCV) polymerase as a drug target for designing non-nucleoside inhibitors, and discusses details related to HCV sequence variation and quasispecies, HCV polymerase structure and mechanism, classes of polymerase inhibitors, inhibitors currently under development, the nature of drug resistance, and the need for combination therapy. Among the non-nucleoside inhibitors, compounds with thiophene carboxylic acid, pyranoindole, dihydropyranone, or phenylalanine scaffolds have been shown to bind to HCV polymerase in the thumb allosteric pocket by X-ray cocrystallization structures. C316Y and G554D appear to be the most important resistance mutations, suggesting overlapping resistance with HCV-796 and likely binding to the HCV polymerase active-site priming nucleotide pocket. Both sequence variations between genotypes and the quasispecies nature of HCV may contribute to drug resistance. Patients may have low levels of preexisting variants in their quasispecies that are resistant to antiviral drugs. These preexisting variants may be selected upon drug treatment and quickly become the dominant species. Many groups have reported on resistant mutants selected with various HCV polymerase inhibitors in vitro using the HCV replicon system. GSK reported several mutants against a benzothiadiazine (Compound 4), including M414T and N411S. Due to the high replication rate of HCV and errorprone nature of HCV polymerase, monotherapy will lead to the selection of preexisting resistance mutations and ultimately to the inability to eradicate HCV.
The discovery of an infectious virus system based on virus from a patient with fulminant hepatitis has created another tool for investigating the viral replication cycle. All of the nucleoside drugs used to treat infections with human immunodeficiency virus (HIV), hepatitis B virus, and herpesviruses can be considered to be 29-deoxynucleoside analogs. Since its nucleotide substrates are ribonucleotides, Hepatitis C virus (HCV) RNA polymerase novel has different substrate specificity regarding substituents at the 29 position of the ribose ring. Thus, it is likely that substituents at the 2' position of the ribose ring of nucleoside analog inhibitors of RNA polymerase that give rise to potent inhibition will be different from those active as inhibitors of DNA polymerase activity. Inhibition of HCV replication at other putative sites of replication such as lymphocytes may also be important to achieve viral clearance. Roche has disclosed the discovery of nucleoside analog inhibitors of HCV replication having modifications at the 4' position. Ribavirin (1-b-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a nucleoside analog with a long history of use as a chemotherapy to treat viral infection with a broad spectrum of activity. Liver biopsy showed hepatic pathogenesis typical of HCV infection. Reisolation of virus used to infect new chimps showed that the H77 strain was infectious in subsequent recipient chimps. It is more difficult to address ribavirin resistance in cell culture because ribavirin is not a very effective replication inhibitor of 1b replicons. Since nucleoside analogs must be converted to the triphosphate, they are inherently prodrugs.
This chapter summarizes many targets for orthopoxviruses that might be exploited in the discovery of additional agents for potential diseases and indicates the mechanisms of action of a number of compounds. The viral DNA polymerase performs a critical role in viral replication, and its susceptibility to nucleoside analogs has made it the dominant target for the development of antiviral drugs. The synthesis of deoxynucleotides is also catalyzed by the heterodimeric ribonucleotide reductase encoded by F4L and I4L. Ribonucleotide reductase converts ribonucleotides to the corresponding deoxyribonucleotides at the level of the diphosphate and supplies deoxyribonucleoside triphosphates to support DNA replication in the cytoplasm. A number of small molecules are known to broadly target protein kinases, and it is possible that medicinal chemistry efforts could identify selective inhibitors. Immature virions containing genomic DNA undergo complex maturation that leads to the condensation of virus cores and involves proteolytic events, the loss of D13, and the formation of new disulfide linkage catalyzed by the viral redox system. The complex replication cycle of the orthopoxviruses requires the concerted activities of numerous viral proteins. The chapter also summarizes each of the stages of viral replication, notes the viral proteins that perform critical functions, and identifies specific inhibitors that affect these processes.
Influenza viruses are classified as type A, B, or C based on antigenic reactions of their internal proteins. Type A influenza viruses are further divided into subtypes according to the antigenic properties of their surface antigens, the glycoproteins hemagglutinin (HA) and neuraminidase (NA). The genome of influenza virus consists of eight segments of single-stranded RNA, ranging in size from ~900 to 2,300 nucleotides. Each RNA segment contains the coding information for one or two proteins, but in the negative sense. The RNA segments are coated with the nucleoprotein (NP), and some are associated with the three subunits of the viral RNA-dependent RNA polymerase complex. The chapter discusses targets for antivirals against influenza. The M2 ion channel is the target of the earliest licensed antiviral drugs against influenza, amantadine and rimantadine. NA is the second most abundant glycoprotein on the virus surface. It cleaves sialic acid residues from glycoproteins and some glycolipids, thus acting as a receptordestroying activity. The cyclopentane peramivir was developed by BioCryst, again based on the crystal structure of NA and its interactions with inhibitors. The aim was to find an inhibitor that was readily synthesized and orally available and that did not induce resistance. The chapter talks about development of antiviral drugs targeted to influenza, and targeting host functions. The diversity of influenza viruses and their capacity to change present a particular challenge to the development and use of anti-influenza antivirals.
Severe acute respiratory syndrome (SARS) is the first new infectious disease of this century, caused by a novel human coronavirus (SARS-CoV), and the disease is associated with severe pulmonary pathological features leading to high mortality. This chapter talks about different kinds of inhibitors such as small-molecule inhibitors, peptide, and papain-like proteinase inhibitors. SARS-CoV is a positive-sense single-stranded (ss) RNA virus. The 30-kb genome is predicted to encode at least 10 open reading frames (ORF), some of which encode proteins involved in virus entry into cells. Receptor-virus interaction can be inhibited using two approaches. First, develop inhibitors that block the cellular receptor with which the virus attachment protein interacts. Second, block the domain in the virus attachment protein that binds to the cellular receptor. Researchers have determined the crystal structures of human coronavirus 3CLpro and suggested that the rhinovirus 3CLpro inhibitor AG7088 could serve as a starting point for an anti-SARS drug based on the theoretical homology model of SARS-CoV 3CLpro. Researchers have showed that the RNAi targeting of the coronavirus RdRp using synthesized short hairpin expression plasmids significantly reduced the expression of target protein in 293 cells and HeLa cells and blocked plaque formation of SARS-CoV in Vero E6 cells. Development of inhibitors of the innate immune response might also be worthwhile, with the caveat that humans, like animals, are reservoirs of mixed infections, latent, chronic, and acute, and that down-regulating an immune response to ameliorate a SARS infection may exacerbate a coexisting infection from another infectious agent.
This chapter discusses the key question of unavailability approved antiviral treatments for flavivirus pathogens which cause significant morbidity and mortality, examines the progress made in the development of therapies, identifies key targets of therapy, and reviews the challenges to overcome in the development of antiflaviviral disease treatments. It deals only with members of the Flavivirus genus, which include viruses of human concern, such as dengue virus (DV), yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Murray Valley encephalitis virus (MVEV), Saint Louis encephalitis virus (SLEV), and tick-borne encephalitis virus (TBEV), all of which cause morbidity and mortality. A few flaviviruses, primarily DV and YFV, cause hemorrhagic manifestations in severe infection. The chapter investigates targets for the treatment of flaviviruses, including viral and host elements that may be effectively targeted for treatment. Important progress in the treatment of flavivirus infections has been made recently, bringing ever closer to fruition the important goal of developing a broad-spectrum agent that is effective after disease manifestation. New animal models of flaviviral disease would be important in developing a better understanding of basic virology and antiviral treatment. Epidemiological methods to detect and predict the severity and location of outbreaks would be beneficial in control of DV diseases, giving better chances to efficacy of antiflaviviral agents. Alerting physicians or veterinarians of emerging flaviviral outbreaks would also help improve the diagnosis and treatment of human or animal infections.
Recently, the most significant progress in knowledge of hepatitis C virus (HCV) biology and interaction with host cells has concerned the role of lipids for genome replication, assembly and egress, and entry into cells. The major hepatic consequence of HCV infection is the progression to cirrhosis and its complications, such as ascites, hepatic insufficiency, and hepatocellular carcinoma (HCC). With the identification in 1989 of HCV as the infectious agent responsible for non-A/non-B hepatitis and the development of specific detection tests, it has become possible to monitor the efficacy of interferon (IFN)-α treatment. With the increased survival associated with the use of highly active antiretroviral therapy (HAART), morbidity and mortality from HCV-induced liver disease have started to increase significantly. Microarray results from liver biopsy tissue taken before therapy in a cohort of patients given pegIFN and ribavirin were recently reported. In this study, patients who were subsequently identified as non-responders had high baseline expression of IFN-stimulated genes (ISGs), whereas responders to therapy more closely resembled healthy controls. Kempf et al. illustrated the need for good knowledge of drug metabolism to improve the efficacy of a drug in vivo. In this study it was shown that a pharmacokinetic enhancement of telaprevir and boceprevir could be achieved by codosing with ritonavir, a potent inhibitor of the cytochrome P450 3A, which is involved in the metabolism of both drugs.
This chapter provides an overview on molecular strategies for prevention of sexually transmitted viral disease. The chapter focuses on the perceived need, basic research challenges, and scientific grounds for confidence in the development of anti-human immunodeficiency virus (HIV) type 1 (HIV-1) microbicides with emphasis on viral/pathogen synergies and mucosal factors of susceptibility. Synergistic mechanisms underlying the phenomenon of "amplified transmission" are discussed in the chapter. Mathematical modeling predicts that even a partial protection would substantially relieve the burden of the HIV pandemic. Nevertheless, because of the viral diversity and the complexity and redundancy of the viral mucosal penetration routes, it is unlikely that a single microbicide or multiple microbicides inhibiting acquisition via a single target would prove to be fully efficient. The major mechanisms of action targeted by microbicides, so far, are degrading or neutralizing the virus before it reaches its target cells, blocking the viral entry and intercellular passage, as well as attacking the intra-cellular steps of the viral cycle, mainly the reverse transcription and viral integration processes. The mechanism of action of the antiretroviral drugs nucleoside and non-nucleoside RT inhibitors (NRTIs and NNRTIs) is discussed in detail. The development of prevention strategies and tools to encompass the global diversity of HIV-1, to be holistically compatible with the wide range of age and multicultural and socioeconomic backgrounds, is a colossal international undertaking that has mobilized scientists, advocates, philanthropists, and policy makers around the world.
Phenotypic susceptibility assays are used in the laboratory to measure the susceptibility of a virus to an antiviral agent. They are used for some viruses, such as human immunodeficiency virus type 1 (HIV-1), in clinical settings to help construct the drug regimen most active against an individual patient’s virus. This chapter summarizes the technology behind commonly used antiviral drug susceptibility assays for HIV-1 and the interpretation of results generated by them. Currently there are two approved anti-HIV drugs that target virus entry: the fusion inhibitor enfuvirtide (ENF) and the CCR5 coreceptor antagonist maraviroc. The chapter describes phenotypic assays for determining HIV-1 coreceptor tropism. Assays that determine HIV-1 viral tropism in a patient are needed to allow the clinician to make an informed decision as to whether a CCR5 co-receptor antagonist is an appropriate drug choice for a given patient. Two standardized MT-2 assay approaches have been described. In the first, viral stocks from stimulated patient lymphocytes co-cultured with lymphocytes from an HIV-negative donor are generated. The second method utilizes direct cocultivation of patient lymphocytes with MT-2 cells, followed by microscopic examination. Currently approved, interferon/ribavirin-based treatment of hepatitis C virus (HCV) infection is incompletely effective and is associated with significant toxicity and tolerability issues. Approaches to measure HCV drug susceptibility can be broadly classified into four categories: (i) intact virus assays, (ii) replicon-based recombinant virus assays (RVAs), (iii) cell-based (nonreplicon) assays, and (iv) enzymatic assays. Phenotypic assays are useful during preclinical development, clinical development, and potentially in clinical practice.
Nucleoside and nucleotide analogs have served as the cornerstones of antiviral therapy against human immunodeficiency virus (HIV), herpesviruses (including herpes simplex virus type 1 [HSV-1], HSV-2, varicella-zoster virus, and cytomegalovirus), and the hepatitis B and C viruses (HBV and HCV, respectively). Rather than providing a comprehensive discussion of the metabolism of individual agents, this chapter gives a general overview of enzymes involved in the metabolism of nucleoside and nucleotide analogs. It also highlights a few examples illustrating the unique pharmacology of the molecules. Competing with anabolism, various modes of catabolism and egress can serve to limit the maximal and temporal levels of the active species in target cells. Antiviral nucleoside and nucleotide analogs represent a large structural diversity with analogs mimicking virtually all the natural ribose and 2'-deoxyribose nucleosides and nucleotides. The importance of the 3' hydroxyl in the interaction of nucleosides with nucleoside transporters may differentiate the distribution of 3'-deoxynucleoside analogs and 3'-hydroxyl-containing nucleoside analogs. Anion and cation transporters with more general substrate specificity have also been identified to interact with nucleosides and nucleotides. In addition to anabolic drug interactions, highly catabolized nucleosides can have their levels altered due to interference with their degradation pathways. Drug interactions due to changes in elimination have also been observed to occur between nucleoside and nucleotide analogs and concomitant agents not related to nucleosides. Successful prodrug strategies promise to more effectively target infected tissues while decreasing exposure to sites of toxicity, offering the potential to increase efficacy while decreasing unwanted side effects.
This chapter provides a general introduction and overview of the interferon (IFN) pathway. Separate sections of this chapter address the different types of IFN, activation of IFN-α/β expression, IFN-mediated signal transduction, antiviral mechanisms, and viral resistance to the IFN-α/β response. The IFNs are classified into three types (I, II, and III) based on receptor usage, sequence homology, and chromosome location of their genes. The chapter primarily focuses on the type I IFNs, as these cytokines are most closely associated with antiviral activity and therapeutic use. Like RNA, cytosolic DNA also induces the production of IFN-β. Therefore, in addition to RNA viruses, a mechanism also exists to detect the genomes from DNA viruses in the cytoplasm of infected cells. The Toll-like receptors (TLRs) are critical for recognizing different molecular patterns that are unique to viral or bacterial pathogens. As with the cytoplasmic sensors, specificity for pathogen-derived nucleic acids by the TLRs is at least in part provided at the level of nucleic acid modifications. IFN-α/β is important for certain aspects of the adaptive immune response and serves as one example of a bridge between innate and adaptive immunity. In addition to antiviral and immunomodulatory functions, IFN-α/β can also negatively influence cellular proliferation. Future research into improved IFN-based antiviral therapies might focus on improving the antiviral properties of these cytokines while decreasing the unwanted side effects. This goal might be accomplished in a number of distinct ways.
This chapter reviews the role of toll-like receptors (TLRs) in innate antiviral responses and in coordinating the antiviral adaptive immune system, and discusses the potential for TLRs as novel molecular targets for antiviral immunomodulatory therapy. A mutation in the Toll gene in Drosophila that results in defective protein was associated with reduced survival after fungal infection. The chapter discusses TLR recognition of pathogen-associated molecular patterns, TLR signaling pathway, biological outcomes of TLR activation, and TLRs and the pathogenesis of selected viral pathogens. The potential role for TLR-7 and TLR-8 in HSV pathogenesis is highlighted by ongoing research efforts to control herpes simplex virus (HSV) infections with the use of small-molecule TLR-7 and TLR-8 agonists. Many viruses, however, have evolved to develop strategies that block the effector mechanisms induced through TLR signaling pathways. Coronavirus, a contagious viral pathogen that causes the highly fatal severe acute respiratory syndrome (SARS), has an attenuated ability to induce type I interferons (IFNs), which are essential for the efficient control of the infection, because it has developed a TLR evasion mechanism characterized by failure of IRF-3 activation. The chapter describes TLRs as targets for immunomodulation and antiviral therapies. The successful clinical development of imiquimod, the prototype TLR immune response-modifying drug, provides a solid example of the promise and remarkable potential that TLR modulators have in bringing novel antiviral therapeutic strategies in the clinical setting.
The human alphaherpesviruses include human herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV). HSV-1 and HSV-2 are responsible for primary and recurrent herpetic lesions of the mouth and genital tract, as well as more serious and potentially life-threatening infections of the eye and central nervous system. This chapter discusses alternative targets for antiherpesviral therapy. The roles of various viral glycoproteins in the attachment and penetration steps at the outset of the infection cycle are only now being identified; however, as with human immunodeficiency virus (HIV), the processes of attachment, receptor recognition, and penetration are likely be excellent targets for the development of antiviral therapy. Several reports have described a class of agents that inhibit the adsorption of the virus to host cells. Viral genes are classified as immediate early, early, or late and are transcribed from both strands of the viral genome by cellular RNA Pol II. The authors have proposed that recombination-dependent DNA replication plays an important role in viral DNA replication. Procapsids formed in the nucleus are competent to undergo encapsidation of the viral genome accompanied by a major conformational change in its structure from a sphere to a more angular shape.
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Our ever-increasing understanding of viral replication, not only in terms of the functions of viral proteins, but also those of cellular ones, has allowed the development of antiviral agents that have proved a real success in the treatment of diseases caused by herpes viruses, human immunodeficiency virus and influenza virus, and it probably will not be long before hepatitis C virus can be added to the list. This book describes the efforts that are being made to identify and validate antiviral targets and evaluate their efficacy in animal models and in the clinic. The critical issue of drug resistance is discussed, as is the possibility of using microbicides to prevent infection. The book contains a wealth of information and I can recommend it to all students, research scientists and clinicians interested in human viral disease and its management. The book's hefty price tag, however, is likely to limit its purchase to institutions.
Society for General Microbiology: Microbiology Today
Reviewer: Christopher Ring, Middlesex University
Review Date: Feb 2009
At A Glance
After fifty years of work on antiviral agents we still have far fewer than are needed. This volume describes antiviral drug discovery from a target-based approach.
Description
This book reviews the biochemical mechanisms of current antiviral agents and examines the approach taken to discover new antiviral agents. It also provides details on the techniques used to discover and test these new compounds.
Purpose
It is designed to bring together research on antiviral agents in a single place and compare the methods used to discover new therapeutic antiviral agents. The compilation of this information in one book will aid other scientist in developing new antiviral agents.
Audience
This will appeal to scientists working on new compounds that act to interrupt the viral pathogenesis pathways. It also might be of interest to those involved in the study of cell processes. It is written by accomplished scientists who work in this area of antiviral drug discovery and would be of interest to more advanced scientists.
Features
The book begins with a review of the first successful antiviral agent used as effective therapy against herpes simplex virus. This sets the stage for the rest of the book. It is clear that the current antiviral agents have had a tremendous impact on the clinical outcome of several well-known viral infections such as human immunodeficiency virus and herpesvirus infection. However, viruses are very fluid and have begun to develop resistance to the current agents, thus new drugs are needed to continue to control these devastating diseases. The discovery of new antiviral agents begins with an understanding of the cellular pathway required for viral replication. New agents can then be designed to block the viral replication without damaging uninfected cells. The remaining chapters describe this discovery process and the potential for new antiviral agents. They also describe the methods used in this endeavor.
Assessment
This book details information on viral pathways in the cell and the mechanism of antiviral action and would be very useful to scientists working on antiviral agents. Most of the chapters address drugs that target HIV and herpesviruses, and there is no data on antiviral agents used to treat hepatitis B, a major viral pathogen.
Doody Enterprises
Reviewer: Rebecca Horvat, PhD, D(ABMM) (University of Kansas Medical Center)
Date Reviewed: May 2009
©Doody’s Review Service