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Antiviral Research (v.71, #2-3)
Introduction to the Special Issue dedicated to Prof. Erik De Clercq for reaching the Professor Emeritus status at the Katholieke Universiteit Leuven
by Jan Balzarini; Graciela Andrei; Lieve Naesens; Johan Neyts; Christophe Pannecouque; Dominique Schols; Robert Snoeck (pp. 75-76).
Aspects of successful drug discovery and development by Rudi Pauwels (pp. 77-89).
Despite landmark achievements (e.g. >20 new anti-HIV drugs), a number of important therapeutic challenges remain. Although an expanding array of new drug discovery technologies has become available, drug research and development (R&D) productivity in general is still low. The establishment of close functional links between specialists active in early discovery, development and the clinic can thereby contribute to overall efficiency and higher success rates of new drug candidates. One of the more qualitative discovery challenges is to improve the predictability of early stage research models in term of in vivo drug efficacy. A cell-based model using viral replication in human T cells (MT-4) is used as an example from the HIV field to highlight the role of cell-based assays as tools for new target discovery, lead finding and optimization. The development of the next generation HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs) TMC125 and TMC278 and the protease inhibitor (PI) TMC114 (Prezista™), further point to new fundamental strategies to combat and prevent antiviral drug resistance and to the importance of incorporating clinical and pharmaceutical aspects into lead finding and optimization, drug design and drug candidate selection. A more parallel-oriented drug discovery strategy is thus portrayed that harnesses some ‘evolutionary’ principles in combination with technologies that are currently rationalizing drug discovery.
Keywords: Chemotherapy; NNRTI; Protease inhibitor; HIV; Drug development
Rational design of polymerase inhibitors as antiviral drugs by Bo Öberg (pp. 90-95).
Almost all viruses have polymerases which are suitable targets for antiviral drugs. The development of selective polymerase inhibitors started with screening of compounds in virus-infected cell cultures and the mechanism of action was investigated once an inhibitor had been found. Especially nucleoside analogs were screened as their triphosphates were potential substrates for polymerases. However, the stepwise phosphorylation by cellular, and sometimes viral, kinases to the active triphosphate prevented a truly rational design of polymerase inhibitors.Nucleotide analogs offers a type of compounds which could be designed in a more rational way than nucleoside analogs since the first, most selective, phosphorylation step is eliminated in the path to the active inhibitor.The development of pyrophosphate analogs made rational design possible since these compounds act directly on the viral enzyme, but the room for structural variation was limited.The non-nucleoside HIV reverse transcriptase inhibitors are direct inhibitors and can thus be designed in a truly rational way by use of structure information on the enzyme-inhibitor complex by use of X-ray and NMR. This rational design of allosteric inhibitors is also being used in the development of inhibitors to other viral polymerases.
Keywords: Rational design of an enzyme inhibitor and rational design of a drug; Types of polymerase inhibitors; Development of nucleoside analogs as polymerase inhibitors; Development of nucleotide analogs as polymerase inhibitors; Development of pyrophosphate analogs as polymerase inhibitors; Development of allosteric polymerase inhibitors
Three-dimensional culture models for human viral diseases and antiviral drug development by Graciela Andrei (pp. 96-107).
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.
Keywords: Three-dimensional culture models; Organotypic cultures; Antivirals
Anti-inflammatory properties of Type I interferons by Alfons Billiau (pp. 108-116).
The notion that Type I interferons (interferon-α and -β) possess anti-inflammatory potential is supported by data from clinical application in multiple sclerosis, by studies on cultured immune-competent cells and by investigation of experimental diseases in whole animals. These observations deserve the attention of virologists for their potential role in the pathogenesis and clinical management of virus infections.
Keywords: Interferon; Inflammation
Antiviral drug resistance by Douglas D. Richman (pp. 117-121).
Almost 30 years ago it was proposed that the selection for antiviral drug resistance should be used as an indicator of antiviral drug activity. In addition to discriminating between cellular toxicity and specific activity directed against a viral target, drug resistant mutants have been used to confirm the mechanism of action of antiviral drugs, to discover the functions of several viral proteins and to provide insights into viral evolution and fitness. Drug resistance has also become a standard component of both the preclinical and clinical drug development process. For HIV and increasingly for other viruses drug resistance testing has become standard-of-care in clinical practice. A few selected examples are provided to illustrate each of these points.
Keywords: Antiviral drugs; Drug resistance; HIV; Influenza; Herpesviruses
Ribonucleotide reductase inhibitors as anti-herpes agents by Stanislaw F. Wnuk; Morris J. Robins (pp. 122-126).
Ribonucleotide reductases (RNRs) supply the 2′-deoxyribonucleotide building blocks for DNA synthesis in mammalian cells and for herpes viruses. The viral-encoded RNRs have unique protein sequences that differ from mammalian enzyme primary structures. Selective inhibition of a viral RNR might provide an approach to new anti-herpes agents with minimal effects on the mammalian host RNRs. This review summarizes efforts to develop anti-herpes agents that selectively target viral-encoded RNRs.
Keywords: Ribonucleotide reductases (RNRs); Heterocyclic thiosemicarbazones; Oligopeptide/peptoid binding to RNR-R2 C-terminal sequences
Herpesvirus latency and therapy—From a veterinary perspective by Hugh J. Field; Subhajit Biswas; Islam T. Mohammad (pp. 127-133).
This short review considers how the human herpesviruses were among the first viruses to be effectively treated by means of antiviral therapy although the ability of alphaherpsviruses to establish neuronal latency with reactivation remains the major obstacle to achieving a cure. Laboratory animals played an essential role in the development of herpes antivirals including our understanding of the complexity of the neurological infection in relation to chemotherapy. The existence of natural herpesvirus infections in domestic species also contributes to our understanding of latency and reactivation relevant to antiviral therapy although the use of antivirals to treat or prevent virus infections in veterinary species has been minimal, to date. The review briefly focuses on herpes infections in the horse and cat where some progress has already been achieved in the veterinary antiviral field.
Keywords: HSV; EHV-1; FHV-1; Veterinary; Antiviral nucleosides; Latency
Tricyclic nucleoside analogues as antiherpes agents by Bozenna Golankiewicz; Tomasz Ostrowski (pp. 134-140).
Tricyclic (T) guanine analogues are a class of compounds in which the N1 and N2 atoms of the guanine system are linked by etheno bridge to form the 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purine system. Almost 70 tricyclic derivatives of guanine-type potent antiherpetic agents acyclovir (ACV), ganciclovir (GCV) and 9-{[cis-1′,2′-bis(hydroxymethyl)cycloprop-1′-yl]methyl}guanine were synthesized and evaluated for activity against viruses of the herpes family. Here, we review the most successful compounds in terms of their antiviral activity and physico-chemical properties. These features are modulated by the kind and position of additional substituents present in the appended third ring of aglycone. The best antiherpetic activity–fluorescence combinations as well as activity of compounds in comparison to parent congeners are summarized. The data presented indicate that compounds of the 6-(4-RPh) family are of particular importance because of their advantageous antiviral potency, increased lipophilicity and good or moderate fluorescence properties.
Keywords: Herpes simplex viruses; Antivirals; Acyclovir; Ganciclovir; Tricyclic analogues; Fluorescence
Herpes simplex encephalitis: Adolescents and adults by Richard J. Whitley (pp. 141-148).
Herpes simplex encephalitis (HSE) remains one of the most devastating infections of the central nervous system despite available antiviral therapy. Children and adolescents account for approximately one third of all cases of HSE. Clinical diagnosis is suggested in the encephalopathic, febrile patient with focal neurologic signs. However, these clinical findings are not pathognomonic because numerous other diseases in the central nervous system can mimic HSE. Neurodiagnostic evaluation can provide support for the diagnosis by the demonstration of temporal lobe edema/hemorrhage by magnetic resonance image scan and spike and slow-wave activity on electroencephalogram. In the current era, the diagnostic gold standard is the detection of herpes simplex virus (HSV) DNA in the cerebrospinal fluid by polymerase chain reaction (PCR). Although PCR is an excellent test and preferable to brain biopsy, false negatives can occur early after disease onset. Acyclovir is the treatment of choice and is administered at 10mg/kg every 8h for 21 days. Even with early administration of therapy after the disease onset, nearly two thirds of survivors have significant residual neurologic deficits. Current investigative efforts are assessing the prognostic value of quantitative PCR detection of viral DNA at the onset of therapy as well as at the completion of therapy and the contribution of prolonged antiviral therapy to improved neurologic outcome.
Keywords: Herpes simplex encephalitis; Cerebrospinal fluid; Polymerase chain reaction
Aryl furano pyrimidines: The most potent and selective anti-VZV agents reported to date by Christopher McGuigan; Jan Balzarini (pp. 149-153).
Bicyclic aryl furano pyrimidines represent the most potent anti-VZV agents reported to date. Lead compounds have EC50 values in vitro as low as 0.1nM and selectivity index values exceeding one million. They have an absolute requirement for VZV thymidine kinase (TK) and most likely act as their phosphate forms. Some structural modification, such as aryl substitution, is tolerated, while little sugar modification is acceptable. We herein summarise their biological profiles and structure activity relationships as discovered to date.
Keywords: Varicella zoster virus; Bicyclic nucleoside analogue; Shingles
Antiviral drugs for cytomegalovirus diseases by Karen K. Biron (pp. 154-163).
Cytomegalovirus infections are associated with severe morbidity and mortality is patients at risk for disease because of immune system disabilities; in particular, recipients of stem cell (HSCT) or solid organ (SOT) transplants. There are three systemic drugs approved for CMV treatment: ganciclovir, or its prodrug valganciclovir, foscarnet, and cidofovir. An anti-sense therapeutic, ISIS 2922, is also approved specifically as in intravitreal treatment for CMV retinitis. Ganciclovir, and more recently, valganciclovir, have been useful in proactive approaches of CMV disease management; in both prophylactic and preemptive regimens in HSCT and SOT populations. The major anti-herpes agent valacyclovir has also been approved for prophylaxis of renal transplant recipients, or SOTs outside of the US. These drugs have provided major advances in CMV disease management, although they are limited by intolerable toxicities, oral bioavailability and efficacy, and risk of drug resistance with extended use. Several drugs are in early clinical development which may address these limitations; this review will provide an overview of our current arsenal of available drugs, and of those in the early clinical development pipeline.
Keywords: CMV; Nucleoside analog; Nucleotide analog; Pyrophosphate analog; Novel benzimidazole riboside antiviral drugs; Alkoxyalkyl esters of cidofovir; Ganciclovir; Valganciclovir; Valaciclovir; Foscarnet
Pivotal role of animal models in the development of new therapies for cytomegalovirus infections by Earl R. Kern (pp. 164-171).
Since human cytomegalovirus (CMV) is extremely species specific and does not replicate in experimental animal tissues, animal models for the evaluation of antiviral agents for these infections have utilized surrogate animal viruses including murine CMV, rat CMV and guinea pig CMV. Murine CMV and rat CMV infections in normal and immunocompromised animals provide models of disseminated infection and are ideal for screening of new agents. While guinea pig CMV infection in immunocompromised animals also provides a model for disseminated disease, the model for congenital CMV is unique among all the experimental models. While these models have played a major role in the development of ganciclovir, foscarnet and cidofovir, they do not provide information directly related to human CMV, nor are they useful for evaluation of agents that are active only against human CMV. The SCID-hu mouse models in which human tissue is infected with human CMV has been very useful in the development of new antiviral agents such as maribavir and cyclopropavir. Collectively these experimental CMV infections provide a variety of models representing various aspects of CMV infection in humans that are highly predictive for antiviral efficacy in humans.
Keywords: Cytomegalovirus; Animal models; Mouse; Rat; Guinea pig
Antiviral therapy for adenovirus infections by L. Lenaerts; L. Naesens (pp. 172-180).
The treatment of severe adenovirus keratoconjunctivitis and life-threatening adenovirus infections in immunocompromised patients is still unsatisfactory. We here review the mode of action and antiviral data for cidofovir and ribavirin, obtained in cell culture, animal models or patients. Several nucleoside or nucleotide analogues have been described that target the adenovirus polymerase, whereas other antiviral targets have been poorly investigated. Furthermore, optimal therapeutic response may be achieved by combining antiviral therapy with immunotherapeutic approaches, as currently being explored.
Keywords: Adenovirus; Immunocompromised host; Antiviral; Cidofovir; Ribavirin; Immunotherapy
Papillomavirus and treatment by Robert Snoeck (pp. 181-191).
Human papillomaviruses (HPVs) are small DNA viruses responsible for a broad range of clinical presentations, characterized histologically by the proliferation of epithelial cells. HPVs are responsible for benign as well as malignant lesions, the most frequent of the latter being cervical carcinoma. A better knowledge of the immunobiology of these lesions allowed the development of prophylactic vaccines (for the most frequent genital types) that are presently under evaluation. The present paper describes different approaches for the treatment of HPV lesions, still mostly based on surgery, and underlines the importance of developing adjuvant therapies.
Keywords: Papillomavirus; Cervical carcinoma; Warts; Vaccines; Cidofovir
Antivirals in the transplant setting by Paul D. Griffiths (pp. 192-200).
Over the past quarter of a century, antiviral drugs have moved from an experimental adventure in transplant patients to a situation where they are used routinely to prevent diseases caused by several viruses. Furthermore, they have significantly reduced several medical complications of transplantation, such as graft rejection, thereby implicating viruses as components of their pathogenesis. By controlling these major complication, the development of these antiviral drugs and their prodrugs, has therefore greatly facilitated the clinical expansion of transplantation, allowing life saving procedures to be offered to more patients who could potentially benefit. This article will briefly summaries which viruses are important following transplantation and outline the evidence-base from randomized controlled clinical trails for the deployment of antiviral drugs to prevent viral diseases.
Keywords: Prophylaxis; Preemptive therapy; Herpesviruses; Evidence-based treatment
Assembling a smallpox biodefense by interrogating 5-substituted pyrimidine nucleoside chemical space by Xuesen Fan; Xinying Zhang; Longhu Zhou; Kathy A. Keith; Earl R. Kern; Paul F. Torrence (pp. 201-205).
The nucleoside 5-formyl-2′-deoxyuridine has been used as a starting point for the generation of novel 5-substituted pyrimidine nucleosides that are shown to possess significant antiviral activity against two representative orthopoxviruses, namely vaccinia virus and cowpox virus.
Keywords: Cowpox virus; Vaccinia virus; Aldehyde; Pyran; Pyrazolone; Multicomponent reaction
Antiviral therapy of chronic hepatitis B by Fabien Zoulim (pp. 206-215).
Treatment of chronic hepatitis B remains a clinical challenge. Long-term viral suppression is a major goal of antiviral therapy to improve the clinical outcome of the patients. Antiviral treatment of chronic hepatitis B relies currently on immune modulators such as interferon alpha and its pegylated form, and viral polymerase inhibitors. Because of the slow kinetics of viral clearance and the spontaneous viral genome variability, viral mutants resistant to nucleoside analogs may be selected. However, the development of new antiviral agents is rapidly improving the offing of therapy of chronic hepatitis B. These new therapeutic advances are reviewed in this manuscript.
Keywords: Chronic hepatitis; HBV; Antivirals
HIV co-receptor inhibitors as novel class of anti-HIV drugs by Dominique Schols (pp. 216-226).
Entry inhibitors constitute a new class of drugs to treat infection by human immunodeficiency virus type 1 (HIV-1). The first member of this class, enfuvirtide, previously known as T-20 and targeting gp41, has now been licensed for therapeutic use. Several other entry inhibitors are in various stages of pre-clinical or clinical development. In this review we focus on the chemokine receptor inhibitors targeting CCR5 and CXCR4 that are the main HIV co-receptors for viral entry.
Keywords: CCR5; CXCR4; Antagonist; HIV; Chemokine receptor; gp120 Envelope
Polycyclic peptide and glycopeptide antibiotics and their derivatives as inhibitors of HIV entry by Maria N. Preobrazhenskaya; Eugenia N. Olsufyeva (pp. 227-236).
Antiviral activity and other biological properties of two groups of polycyclic peptides are discussed. Antibiotics of the complestatin–kistamycin group have a structural motif similar to that of the peptide core of antibacterial antibiotics of the vancomycin–teicoplanin group though no amino acid component in the chloropeptin–kistamicin antibiotics is identical to an amino acid incorporated in the peptide core of the antibiotics of the vancomycin–teicoplanin group. Chloropeptins and the hydrophobic several derivatives of antibacterial antibiotics are inhibitors of HIV and some other viruses. They interfere with the viral (i.e. HIV) entry process. Chemical modifications of natural glycopeptide antibiotics led to the compounds with antiviral properties whereas antibacterial properties were lost. These glycopeptide aglycons derivatives can be envisaged as potential lead compounds for application as microbicides against sexual HIV transmission.
Keywords: Complestatin; Kistamicin; Vancomycin; Eremomycin; Hydrophobic derivatives; Viral entry
Inhibition of HIV entry by carbohydrate-binding proteins by J. Balzarini (pp. 237-247).
Carbohydrate-binding proteins (CBP) can be isolated from a variety of species, including procaryotes (i.e. cyanobacteria), sea corals, algae, plants, invertebrates and vertebrates. A number of them, in particular those CBP that show specific recognition for mannose (Man) and N-acetylglucosamine (GlcNAc) are endowed with a remarkable anti-HIV activity in cell culture. The smallest CBP occur as monomeric peptides with a molecular weight of ∼8.5kDa. Many others are functionally dimers, trimers or tetramers, and their molecular weight can sometimes largely exceed 50kDa. CBP can contain 2 to up to 12 carbohydrate-binding sites per single molecule, depending on the nature of the lectin and its oligomerization state. CBP qualify as potential anti-HIV microbicide drugs because they not only inhibit infection of cells by cell-free virus (in some cases in the lower nano- or even subnanomolar range) but they can also efficiently prevent virus transmission from virus-infected cells to uninfected T-lymphocytes. Their most likely mechanism of antiviral action is the interruption of virus entry (i.e. fusion) into its target cell. CBP presumably act by direct binding to the glycans that are abundantly present on the HIV-1 gp120 envelope. They may cross-link several glycans during virus/cell interaction and/or freeze the conformation of gp120 consequently preventing further interaction with the coreceptor. Several CBP were shown to have a high genetic barrier since multiple (≥5) glycan deletions in the HIV envelope are necessary to provoke a moderate level of drug resistance. CBP are the prototypes of conceptionally novel chemotherapeutics with a unique mechanism of antiviral action, drug resistance profile and an intrinsic capacity to trigger a specific immune response against HIV strains after glycan deletions on their envelope occur in an attempt to escape CBP drug pressure.
Keywords: Carbohydrate-binding agents (CBA); Carbohydrate-binding proteins (CBP); Lectins; HIV; Virus entry; gp120 envelope
Antiviral acyclic nucleoside phosphonates structure activity studies by AntonÃn Holý (pp. 248-253).
This review concerns acyclic nucleoside phosphonates (ANP) and describes the concept of the design of isopolar and isosteric nucleotide analogues resistant towards degradation by enzymes in vivo. It describes the development of research which led to the discovery of several structurally related potent antivirals and ultimately resulted in the development of drugs directed against HIV, HBV and DNA-virus infections in general, namely adefovir, cidofovir and tenofovir. In addition to these “classical compounds� the review describes the present development in the field of ANP, the “open-ring ANP� and discusses the present achievements, concept of prodrug design and application.
Keywords: Acyclic nucleotide analogues; Adefovir; Cidofovir; Tenofovir; Open-ring ANP analogues
Perspectives on the development of acyclic nucleotide analogs as antiviral drugs by William A. Lee; John C. Martin (pp. 254-259).
The development of Viread® (tenofovir disoproxil) for HIV and Hepsera® (adefovir dipivoxil) for HBV presented many unique challenges. Unlike nucleosides and most conventional drugs, the parent acyclic nucleotide analogs are charged at physiologic pH and not suitable for oral administration which is highly desired in chronic therapies. Physicochemical properties, cellular permeation, renal toxicity, and bioavailability all had to be addressed during the development of these compounds. As a class, the acyclic nucleotides have long intracellular half-lives, allowing once-daily dosing, which provided the initial rationale for treatment of chronic viral diseases such as HIV and HBV. Prodrugs originally designed to deliver the parent acyclic nucleotide analog to the systemic circulation, also function to increase the tissue distribution and intracellular concentrations of the acyclic nucleotide diphosphate inside cells.
Keywords: Tenofovir; Adefovir; Antiviral drug; Nucleotide; Prodrug; Intracellular; Acyclic nucleotide analog
Dimerization inhibitors of HIV-1 reverse transcriptase, protease and integrase: A single mode of inhibition for the three HIV enzymes? by MarÃa-José Camarasa; Sonsoles Velázquez; Ana San-Félix; MarÃa-Jesús Pérez-Pérez; Federico Gago (pp. 260-267).
The genome of human immunodeficiency virus type 1 (HIV-1) encodes 15 distinct proteins, three of which provide essential enzymatic functions: a reverse transcriptase (RT), an integrase (IN), and a protease (PR). Since these enzymes are all homodimers, pseudohomodimers or multimers, disruption of protein–protein interactions in these retroviral enzymes may constitute an alternative way to achieve HIV-1 inhibition. A growing number of dimerization inhibitors for these enzymes is being reported. This mini review summarizes some approaches that have been followed for the development of compounds that inhibit those three enzymes by interfering with the dimerization interfaces between the enzyme subunits.
Keywords: HIV-1; Reverse transcriptase; Integrase; Protease
The history of N-methanocarbathymidine: The investigation of a conformational concept leads to the discovery of a potent and selective nucleoside antiviral agent by Victor E. Marquez; Stephen H. Hughes; Shizuko Sei; Riad Agbaria (pp. 268-275).
Conformationally locked (North)-methanocarbathymidine (N-MCT) and (South)-methanocarbathymidine (S-MCT) have been used to investigate the conformational preferences of kinases and polymerases. The herpes kinases show a distinct bias for S-MCT, while DNA polymerases almost exclusively incorporate the North 5′-triphosphate (N-MCT-TP). Only N-MCT demonstrated potent antiviral activity against herpes simplex viruses (HSV-1 and 2) and Kaposi's sarcoma-associated herpesvirus (KSHV). The activity of N-MCT depends on its metabolic transformation to N-MCT-TP by the herpes kinases (HSV-tk or KSHV-tk), which catalyze the mono and diphosphorylation steps; cellular kinases generate the triphosphate. N-MCT at a dose of 5.6mg/kg was totally protective for mice inoculated intranasally with HSV-1. Tumor cells that are not responsive to antiviral therapy became sensitive to N-MCT if the cells expressed HSV-tk. N-MCT given twice daily (100mg/kg) for 7 days completely inhibited the growth of MC38 tumors derived from cells that express HSV-tk in mice while exhibiting no effect on tumors derived from non-transduced cells. After i.p. administration, N-MCT was rapidly absorbed and distributed in all organs examined with slow penetration into brain and testes. N-MCT-TP was also a potent inhibitor of HIV replication in human osteosarcoma (HOS) cells expressing HSV-tk.
Keywords: Herpes simplex virus; Kaposi's sarcoma-associated herpesvirus; Kinases; DNA polymerases; HIV reverse transcriptase; Delayed chain termination
l-Nucleoside enantiomers as antivirals drugs: A mini-review by Christophe Mathé; Gilles Gosselin (pp. 276-281).
The discovery that some nucleoside analogues endowed with the unnaturall-configuration can possess biological activities has been a significant breakthrough in antiviral chemotherapy. In this regard, lamivudine (3TC) was the firstl-nucleoside enantiomer approved against HIV and HBV, and several otherl-nucleosides are currently under clinical development as antiviral agents
Keywords: Abbreviations; HIV; human immunodeficiency virus; HBV; hepatitis B virus; HCV; hepatitis C virus; HSV; herpes simplex virus; HCMV; human cytomegalovirus; EBV; Epstein-Barr virus; VZV; Varicella-Zoster virus; RSV; respiratory syncitial virusl; -Nucleoside enantiomers; Antiviral drugs
Application of the cycloSal-prodrug approach for improving the biological potential of phosphorylated biomolecules by C. Meier; J. Balzarini (pp. 282-292).
Pronucleotides represent a promising tool to improve the biological activity of nucleoside analogs in antiviral and cancer chemotherapy. The cycloSal-approach is one of several conceptually different pronucleotide systems. This approach can be applied to various nucleoside analogs. A salicyl alcohol as a cyclic bifunctional masking unit is used, and shown to afford a chemically driven release of the particular nucleotide from the lipophilic phosphate triester precursor molecule. A conceptual extension of the cycloSal-approach results in the design of “lock-in�- cycloSal-derivatives. The cycloSal-approach is not restricted to the delivery of bioactive nucleotides but also useful for the intracellular delivery of hexose-1-phosphates.
Keywords: Nucleoside analogs; Antiviral agent; cyclo; Sal-pronucleotides; Carbohydrate drugs
Therapeutic strategies towards HIV-1 infection in macrophages by Carlo Federico Perno; Valentina Svicher; Dominique Schols; Michela Pollicita; Jan Balzarini; Stefano Aquaro (pp. 293-300).
It is widely recognized that macrophages (M/M) represent a crucial target of HIV-1 in the body and play a pivotal role in the pathogenic progression of HIV-1 infection. This strongly supports the clinical relevance of therapeutic strategies able to interfere with HIV-1 replication in M/M. In vitro studies showed that nucleoside analogue inhibitors of HIV-1 reverse transcriptase have potent antiviral activity in M/M, although the limited penetration of these compounds in sequestered body compartments and low phosphorylation ability of M/M, suggest that a phosphonate group linked to NRTIs may confer greater anti-HIV-1 activity in M/M. Differently, the antiviral activity of non-nucleoside reverse transcriptase inhibitors in M/M is similar to that found in CD4+ lymphocytes. Interestingly, protease inhibitors, acting at a post-integrational stage of HIV-1 life-cycle are the only drugs active in chronically infected M/M. A careful analysis of the distribution of antiviral drugs, and the assessment of their activity in M/M, represent key factors in the development of therapeutic strategies aimed to the treatment of HIV-1-infected patients. Moreover, testing new and promising antiviral compounds in such cells may provide crucial hints about their efficacy in patients infected by HIV.
Keywords: HIV-1; Macrophages; CD4+ lymphocytes; Antiretroviral drugs
Recent status of HIV-1 gene expression inhibitors by Masanori Baba (pp. 301-306).
Human immunodeficiency virus type 1 (HIV-1) gene expression and transcription is a crucial step in the viral replication cycle, which is considered to be a potential target for inhibition of HIV-1. Among the factors involved in this step, the cellular protein nuclear factor (NF)-κB is the most powerful inducer of HIV-1 gene expression. On the other hand, the viral protein Tat plays a central role in sustaining a high level of HIV-1 replication. Several compounds have been reported to selectively inhibit the functions of Tat and NF-κB. Tat inhibitors target either the Tat/TAR RNA interaction or the Tat cofactor cyclin-dependent kinase 9/cyclin T1. Antioxidants, protein kinase C inhibitors, and IκB kinase inhibitors are known to suppress the activation of NF-κB. Although some of the compounds inhibit HIV-1 replication in cell cultures at low concentrations, they also have considerable toxicity to the host cells. Considering the increase of treatment failure cases in highly active antiretroviral therapy due to the emergence of multidrug resistance, HIV-1 gene expression inhibitors should be extensively studied as alternative approach to effective anti-HIV-1 chemotherapy.
Keywords: Abbreviations; HAART; highly active antiretroviral therapy; HIV-1; human immunodeficiency virus type 1; TAR; transactivation response; P-TEFb; positive transcription elongation factor b; CycT1; cyclin T1; CDK9; cyclin-dependent kinase 9; CTD; carboxy-terminal domain; PBMC; peripheral blood mononuclear cell; NF-κB; nuclear factor κB; TNF; tumor necrosis factor; IL; interleukin; LTR; long terminal repeat; PKC; protein kinase C; NADA; N; -arachidonoyldopamine; MAP; mitogen-activated proteinHIV-1; Chemotherapy; Transcription; Tat; NF-κB
Oligonucleotides as antivirals: Dream or realistic perspective? by Arthur Van Aerschot (pp. 307-316).
Many reports have been published on antiviral activity of synthetic oligonucleotides, targeted to act either by a true antisense effect or via non-sequence specific interactions. This short review will try to evaluate the current status of the field by focusing on the effects as reported for inhibition of either HSV-1, HCMV or HIV-1. Following an introduction with a historical background and a brief discussion on the different types of constructs and mechanisms of action, the therapeutic potential of antisense oligonucleotides as antivirals, as well as possible pitfalls upon their evaluation will be discussed.
Keywords: Antisense oligonucleotides; Antiviral activity; HSV-1; HCMV; HIV-1
The interplay between antiviral activity, oligonucleotide hybridisation and nucleic acids incorporation studies by Piet Herdewijn (pp. 317-321).
Nucleoside analogues have been the most successful antiviral compounds. Likewise, they are the most intriguing antiviral compounds, because of their structural relationship to natural nucleosides. This is also the reason why the design process of a potential selective antiviral nucleoside is so difficult. Too many natural processes (from cellular uptake to DNA incorporation) and too many enzymes are involved in their biological effect (activity/toxicity/catabolism/anabolism) to make the design process readily predictable. The relationship between the physicochemical and biochemical properties of nucleoside analogues and their antiviral activity is very complex and could only be understood on a very long term basis. Here we try to explain some of the reasoning that was made during the design process leading to new potent antivirals with a phosphonate functionality.
Keywords: Abbreviations; HIV; human immunodeficiency virus; HSV; herpes simplex virus; CeNA; cyclohexenyl nucleic acids; TNA; threose nucleic acids; HNA; hexitol nucleic acids; RT; reverse transcriptaseHSV; HIV oligonucleotides; Polymerase; Reverse transcriptase; Hexitol nucleoside; Cyclohexenyl nucleoside; Threosyl nucleosides
Pharmacology of current and promising nucleosides for the treatment of human immunodeficiency viruses by Raymond F. Schinazi; Brenda I. Hernandez-Santiago; Selwyn J. Hurwitz (pp. 322-334).
Nucleoside antiretroviral agents are chiral small molecules that have distinct advantages compared to other classes including long intracellular half-lives, low protein binding, sustained antiviral response when a dose is missed, and ease of chemical manufacture. They mimic natural nucleosides and target a unique but complex viral polymerase that is essential for viral replication. They remain the cornerstone of highly active antiretroviral therapy (HAART) and are usually combined with non-nucleoside reverese transcriptase and protease inhibitors to provide powerful antiviral responses to prevent or delay the emergence of drug-resistant human immunodeficiency virus (HIV). The pharmacological and virological properties of a selected group of nucleoside analogs are described. Some of the newer nucleoside analogs have a high genetic barrier to resistance development. The lessons learned are that each nucleoside analog should be treated as a unique molecule since any structural modification, including a change in the enantiomeric form, can affect metabolism, pharmacokinetics, efficacy, toxicity and resistance profile.
Keywords: Antiviral agents; Pharmacology; Nucleoside analogs; HIV
Algorithms for the interpretation of HIV-1 genotypic drug resistance information by Jurgen Vercauteren; Anne-Mieke Vandamme (pp. 335-342).
Drug resistance testing has proven its use to guide treatment decisions in HIV-1 infected patients. Genotyping is the preferred technique for clinical drug resistance testing. Many factors complicate the interpretation of mutations towards therapy response, such that an interpretation system is necessary to help the clinical virologist. No consensus interpretation exists to date and experts often have quite different opinions. As a result, several algorithms for the interpretation of HIV-1 genotypic drug resistance information have been designed. Clinical evaluation of their genotypic interpretation is not always straightforward. We describe a few publicly available systems and their clinical evaluation. We also stress that in addition to drug resistance, for effective management of HIV infection the clinician needs to take into account all potential causes of treatment failure. Successful therapy heavily relies on the expertise of the clinician.
Keywords: HIV; Drug resistance; Interpretation system; Algorithm; Genotype; Phenotype
Is HIV drug resistance a limiting factor in the development of anti-HIV NNRTI and NRTI-based vaginal microbicide strategies? by Jorge Martinez; Paul Coplan; Mark A. Wainberg (pp. 343-350).
Antiviral drugs that act at specific sites within the HIV life cycle have important rationale for development as anti-HIV microbicides. However, to be effective, such drugs must act by directly interfering with viral enzymatic function and eliminate the ability of HIV to mediate infection. Compounds that are developed as microbicides must have high potency, and should ideally not be well absorbed from the vaginal cavity in order to minimize any potential problems of drug resistance. Such compounds should also be active over long periods of time and should be able to be combined with other active agents, in order to promote the concept of synergy, such as that which has been demonstrated in HIV therapeutic studies.
Keywords: HIV drug resistance; Microbicides; NNRTIs; NRTIs
Recent development of therapeutics for chronic HCV infection by Zhuhui Huang; Michael G. Murray; John A. Secrist III (pp. 351-362).
The global prevalence of hepatitis C virus (HCV) infection and serious health consequences associated with chronic state of the disease have become a significant health problem worldwide. Currently, there is no vaccine to prevent the disease and no specific antiviral drug directed against HCV infection. The current standard of care, interferon-based therapies, both alone or in combination with ribavirin, has demonstrated limited success and is associated with undesirable side effects. Thus, the treatment of the chronic HCV infection represents an unmet medical need. With advances in the understanding of HCV replication and the crystal structures of the virally encoded enzymes, the HCV NS3/4A serine protease and the NS5B RNA-dependent RNA polymerase have emerged as ideal targets toward the control of the disease and the development of new anti-HCV agents. In this review, we will summarize the current treatment options, and outline the approaches toward discovery of small molecule antivirals against the virally encoded enzymes. The current clinical studies of promising lead compounds are also reviewed.
Keywords: Hepatitis C virus (HCV); NS3 serine protease; NS5B RNA-dependent RNA polymerase; Target for antiviral therapy; Drug resistance
Selective inhibitors of hepatitis C virus replication by Johan Neyts (pp. 363-371).
Worldwide over 170 million people are chronically infected with the hepatitis C virus and hence at high risk to develop fatal liver disease. There is no vaccine available and the standard therapy [(pegylated) interferon alfa plus ribavirin] is only effective in 50–60% of patients and is associated with important side-effects. The discovery of novel antiviral strategies to selectively inhibit HCV replication has long been hindered by the lack of convenient cell culture models for the propagation of HCV. This hurdle has been overcome first with the establishment of the HCV replicon system in 1999 and, in 2005, with the development of robust HCV cell culture models. In recent years also mouse models have been elaborated that will be instrumental in assessing the in vivo efficacy of novel drugs. The viral serine protease and the viral RNA dependent RNA polymerase have shown to be excellent targets for selective anti-HCV therapy. Clinical studies with a limited number of HCV protease and polymerase inhibitors resulted in encouraging results. However, and not unexpected, preclinical evidence suggest that the virus may become rapidly resistant to such inhibitors. Combination therapy of drugs with different mode of action and resistance profiles may thus be required. Alternative strategies, such as the use of non-immunosuppressive cyclosporin A analogues with potent anti-HCV activity, may prove important, in particular since such compounds may have a resistance profile that is very different from that of protease or polymerase inhibitors.
Keywords: Hepatitis C virus; Protease inhibitors; Polymerase inhibitors; Animal model; HCV cell culture model
Antivirals for influenza: Historical perspectives and lessons learned by Frederick G. Hayden (pp. 372-378).
The development of the currently available classes of antivirals, the M2 proton channel inhibitors and the neuraminidase inhibitors, provides valuable perspectives relevant to the field of antiviral chemotherapy in general and insights into aspects of viral pathogenesis and antiviral resistance relevant specifically to influenza. The efficacy observed with these antiviral drugs has proven the importance of these antiviral targets, as well as the principle that chemoprophylaxis and early treatment are possible in influenza infections with small molecular weight inhibitors.
Keywords: Influenza; Neuraminidase; Amantadine; Oseltamivir; Zanamivir; Pathogenesis; Antiviral resistance
Respiratory syncytial virus infections: Recent prospects for control by Robert W. Sidwell; Dale L. Barnard (pp. 379-390).
Respiratory syncytial virus (RSV) infections remain a significant public health problem throughout the world, although recently developed and clinically approved anti-RSV antibodies administered prophylactically to at-risk populations appear to have significantly affected the disease development. Much effort has been expended to develop effective anti-RSV therapies, using both in vitro assay systems and mouse, cotton rat, and primate models, with several products now in various stages of clinical study. Several products are also being considered for the treatment of clinical symptoms of RSV. In this review, updates on the status of the approved anti-RSV antibodies, ribavirin, and recent results of studies with potential new anti-RSV compounds are summarized and discussed.
Keywords: Respiratory syncytial virus; Antivirals; Review
Rhinovirus chemotherapy by Amy K. Patick (pp. 391-396).
Human rhinoviruses (HRV), members of the Picornaviridae family, are comprised of over 100 different virus serotypes. HRV represent the single most important etiological agents of the common cold [Arruda, E., Pitkaranta, A., Witek Jr., T.J., Doyle, C.A., Hayden, F.G., 1997. Frequency and natural history of rhinovirus infections in adults during autumn. J. Clin. Microbiol. 35, 2864–2868; Couch, R.B., 1990. Rhinoviruses. In: Fields, B.N., Knipe, D.M. (Eds.), Virology. Raven Press, New York, pp. 607–629; Turner, R.B., 2001. The treatment of rhinovirus infections: progress and potential. Antivir. Res. 49 (1), 1–14]. Although HRV-induced upper respiratory illness is often mild and self-limiting, the socioeconomic impact caused by missed school or work is enormous and the degree of inappropriate antibiotic use is significant. It has been estimated that upper respiratory disease accounts for at least 25 million absences from work and 23 million absences of school annually in the United States [Anzueto, A., Niederman, M.S., 2003. Diagnosis and treatment of rhinovirus respiratory infections. Chest 123 (5), 1664–1672; Rotbart, H.A., 2002. Treatment of picornavirus infections. Antivir. Res. 53, 83–98]. Increasing evidences also describe the link between HRV infection and more serious medical complications. HRV-induced colds are the important predisposing factors to acute otitis media, sinusitis, and are the major factors in the induction of exacerbations of asthma in adults and children. HRV infections are also associated with lower respiratory tract syndromes in individuals with cystic fibrosis, bronchitis, and other underlying respiratory disorders [Anzueto, A., Niederman, M.S., 2003. Diagnosis and treatment of rhinovirus respiratory infections. Chest 123 (5), 1664–1672; Gern, J.E., Busse, W.W., 1999. Association of rhinovirus infections with asthma. Clin. Microbiol. Rev. 12 (1), 9–18; Pitkaranta, A., Arruda, E., Malmberg, H., Hayden, F.G., 1997. Detection of rhinovirus in sinus brushings of patients with acute community-acquired sinusitis by reverse transcription-PCR. J. Clin. Microbiol. 35, 1791–1793; Pitkaranta, A., Virolainen, A., Jero, J., Arruda, E., Hayden, F.G., 1998. Detection of rhinovirus, respiratory syncytial virus, and coronavirus infections in acute otitis media by reverse transcriptase polymerase chain reaction. Pediatrics 102, 291–295; Rotbart, H.A., 2002. Treatment of picornavirus infections. Antivir. Res. 53, 83–98]. To date, no effective antiviral therapies have been approved for either the prevention or treatment of diseases caused by HRV infection. Thus, there still exists a significant unmet medical need to find agents that can shorten the duration of HRV-induced illness, lessen the severity of symptoms, minimize secondary bacterial infections and exacerbations of underlying disease and reduce virus transmission. Although effective over-the-counter products have been described that alleviate symptoms associated with the common cold [Anzueto, A., Niederman, M.S., 2003. Diagnosis and treatment of rhinovirus respiratory infections. Chest 123 (5), 1664–1672; Gwaltney, J.M., 2002a. Viral respiratory infection therapy: historical perspectives and current trials. Am. J. Med. 22 (112 Suppl. 6A), 33S–41S; Turner, R.B., 2001. The treatment of rhinovirus infections: progress and potential. Antivir. Res. 49 (1), 1–14; Sperber, S.J., Hayden, F.G., 1988. Chemotherapy of rhinovirus colds. Antimicrob. Agents Chemother. 32, 409–419], this review will primarily focus on the discovery and development of those agents that directly or indirectly impact virus replication specifically highlighting new advances and/or specific challenges with their development.
Keywords: Rhinovirus; Antiviral therapy
Coronaviruses and their therapy by Bart L. Haagmans; Albert D.M.E. Osterhaus (pp. 397-403).
Coronaviruses may cause respiratory, enteric and central nervous system diseases in many species, including humans. Until recently, the relatively low burden of disease in humans caused by few of these viruses hampered development of coronavirus specific therapeutics. However, the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) has prompted the discovery of such drugs. Subsequent studies in animal models demonstrated the efficacy of SARS-CoV specific monoclonal antibodies, pegylated-interferon-α and siRNAs against SARS-CoV. Furthermore, several antivirals shown to be effective against other viruses were tested in vitro. Because of availability and shown efficacy, the use of interferons may be considered should SARS-CoV or a related coronavirus (re)-emerge. The more recent design of wide-spectrum inhibitors targeting the coronavirus main proteases may lead to the discovery of new antivirals against multiple coronavirus induced diseases.
Keywords: Coronaviruses; SARS; Antivirals; Therapy