Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 9, Issue 2, 2009

This special issue of the international journal ‘Infectious disorders - Drug targets’ brings together some of the most famous scientific researchers and clinicians worldwide, who have made major contributions and discoveries in their respective fields of virology. With eleven review articles, the special issue is a real gem covering the latest state of knowledge for each type of pathogenic viruses. Interestingly, it not only deals with currently available therapies, but also focuses on present and ‘future’ molecular targets of the candidate chemotherapeutic drugs that will be potentially developed in upcoming effective or improved antiviral treatments. Basically, the strategy of prospecting ‘novel’ routes of possible molecular targets for antivirals reveals to be crucial regarding the existence and tremendous spread of a variety of viruses with profiles of multiple resistance to drugs. Recently, the Nobel prize in Physiology or Medicine (2008) has been awarded to distinguished virologists for their pioneer works on human immunodeficiency (Drs. Barre-Sinoussi and Montagnier) and papilloma (Dr. zur Hausen) viruses causing AIDS and cervical cancer, respectively. I would like to dedicate this particular issue to those experts (and especially to Dr. Montagnier I collaborated with in the early days of HIV discovery), as well as to other less reknown scientists who daily join their research efforts to fight against viral and non-viral human pathogens, that are likely to represent the 21st century plague.

Chikungunya virus is a typical emerging virus which has been responsible for several million cases of human infections since 2004. No antiviral treatment is currently available. The antimalarial chloroquine has been used in the past but recent studies suggest that it is not or poorly active in vivo. A number of tracks are currently under investigation (inhibition of viral enzymes, of virus entry or maturation, enhancement of immunological response) and new animal models have been made available, including a mouse model and a non-human primate model. We review here the main perspectives of chikungunya antiviral treatment.

Hepatitis B virus infection (HBV) is a significant global health problem. Despite the success of universal hepatitis B vaccination in many countries, more than 350 million individuals worldwide are chronically infected and 15- 40% of those will develop cirrhosis and/or hepatocellular carcinoma if left untreated. Available therapies for chronic hepatitis B (CHB) infection are effective at decreasing viremia and improving measured clinical outcomes, however, no single therapy is optimal. As such, alternative drug therapies and the investigation of their role in the management of CHB are warranted. Significant improvements in the understanding of the HBV life cycle, viral genomics, and virus-host interactions continue to lead to the development of novel viral targets and immune modulators. Currently, two major classes of agents are utilized in CHB: the interferons and the nucleos(t)ide analogues. Each agent has individual advantages and drawbacks. The development of specific antiviral therapy has led to the emergence of HBV drug-resistant strains that has limited the long-term therapeutic potential of available agents. This necessitates the development of new agents that target both wild-type and drug-resistant strains. Further understanding of the basic mechanisms and clinical nuances of drug therapy is warranted. As most novel therapies are in the earliest stages of clinical development and testing, in the near future, treatment will continue to be long-term and likely involve the use of combination therapies to prevent viral resistance. In this review, we will highlight the HBV life cycle and genome, focusing in on current and potential novel antiviral drug targets as well as the benefits and clinical challenges with these therapies.

Herpes simplex virus (HSV) and Epstein Barr Virus (EBV) are Herpesviridae. Although infections are often subclinical, HSV can cause mild to severe diseases, especially in immunocompromised patients. EBV infections are also often asymptomatic but this virus may be associated to carcinoma in immunocompetent patients and to severe diseases in immunocompromised patients. These viruses establish latency, in neuronal cells for HSV and in B-cells for EBV, and may reactivate, with or without symptoms. There are few drugs licensed for the treatment of HSV infections. Most of them target the viral DNA polymerase, in which acyclovir remains the reference treatment some thirty years after its discovery. The emergence of resistant viral strains, mainly in immunocompromised patients, highlights the crucial need for the development of new anti-herpes drugs that can inhibit infection by both wild-type viruses and acyclovir-resistant strains. No antiviral drug has been yet licensed for EBV. Therapies mainly rely on control of immunosuppression and/or immunotherapies. Antiviral drug such as acyclovir and ganciclovir have been used with limited impact except when used with drugs that induce EBV lytic cycle. Over the last few years, significant efforts have been made to set up a range of strategies for the identification of potential new antiviral drugs. For HSV, and more strikingly for EBV, there is a crucial need for antiviral drug active on latent virus. One alternative is to develop drugs with different mechanisms of action. The present article reviews potential targets, viral and cellular, for which specific inhibitors have been identified.

Human Rhinoviruses (HRV) are by far the most common respiratory viruses responsible for most cases of the common cold and important pathogens in acute exacerbations of asthma and COPD. The molecular pathogenesis of HRV infection is quite completely understood. However there is still no approved specific treatment against HRV infections. The aim of this article is therefore to give an overview of the principles of rhinovirus infection, the associated therapeutic targets and to review up-to-date virus-specific clinical trials.

The Flaviviridae family comprises the genus Flavivirus, Hepacivirus and Pestivirus. These viruses are responsible for considerable human and animal disease and mortality worldwide. Flaviviruses cause a range of acute febrile illnesses along with encephalitic or haemorrhagic diseases. Chronic hepatitis C virus (HCV) infection is the most important hepacivirus human disease and remains a global health threat with nearly 200 million carriers worldwide. Current treatment consists in the use of peginterferon alfa (pegIFN) plus ribavirin (RBV) for 24 to 72 weeks, depending on HCV genotype, baseline viral load and the achievement of rapid virological response during therapy. However, current hepatitis C therapy fails to eradicate HCV in nearly half of treated patients and is hampered by relatively serious adverse events. No effective antiviral therapy is currently available for the treatment of flaviviruses or pestiviruses. Following the relative success of antiretroviral therapy against HIV infection, rapid progresses have been made in the development of specifically targeted antiviral therapies against HCV (STAT-C) and other Flaviviridae agents. Drug discovery for HCV is currently particularly exciting, since inhibitors of the HCV serine protease and the RNA-dependent RNA polymerase have recently entered the late stages of clinical development.

Among emergent and re-emergent viral infections, influenza, hemorrhagic fevers, including hantaviruses, constitute one of the major threats to human beings. Advances in immunopathogenesis of these viral infections have improved initial supportive treatments and led to recognition and adoption of several useful antiviral agents. This review focuses on therapeutic and preventive aspects of these viral infections, and evaluates old and new promising agents are in the pipeline of pharmaceutical companies, and finally addresses therapeutic aspects in the treatment of these viral pathogens. However, it should be stressed that only prevention based in particular on research and development of new vaccines may be able in future to control and eventually eradicate these deadly viral pathogens.

Human T-lymphotropic virus type 1 (HTLV-1), the first known human retrovirus, induces various human diseases with a long latency period. The mechanism by which the virus causes diseases is still unknown. Studies indicate that viral replication is important at least for the development of HTLV-1 associated myelopathy, and therefore treatments based on our knowledge of human immunodeficiency virus type-1 (HIV-1) can be utilized to develop potent antiretroviral therapies targeting the replication enzymes reverse transcriptase, protease and integrase as well as the envelope glycoproteins. Furthermore, accessory gene products such as Tax and HBZ may also provide targets for chemotherapy. Treatment targeting these viral proteins may prevent the development of other HTLV-1-related diseases including adult Tcell leukemia, although such treatment may not be useful during the progression of the disease. This review describes the characteristics of HTLV-1 replication enzymes, envelope glycoproteins, and accessory proteins Tax and HBZ, and discusses the status of drug development strategies.

HIV-1 drug regimens now offer more potent, less toxic and more durable choices. However, strategies addressing convenient sequential use of active antiretroviral combinations are rarely presented in the literature. Studies have seldom directly addressed this issue, despite it being a matter of daily use in clinical practice. This is, in part, because of the complexity of HIV-1 resistance information. Nevertheless, several principles can effectively assist the planning of antiretroviral drug sequencing. The introduction of tenofovir, abacavir and emtricitabine into current nucleoside backbone options, with each of them selecting for an individual pattern of resistance mutations, now permits sequencing in the context of previously popular thymidine analogs (zidovudine and stavudine). Similarly, newer ritonavir-boosted protease inhibitors could be potentially sequenced in a manner that uses the least cross-resistance prone PI at the start of therapy while leaving the most cross-resistance prone drugs for later, as long as there is rationale to employ such a compound because of its utility against commonly observed drug-resistant forms of the virus. The ability to sequence new therapies will be enhanced by availability of new antiretroviral drugs.

The development of antiviral drugs for Ebola and Marburg viruses has been slow. To date, beyond supportive care, no effective treatments, prophylactic measures, therapies, or vaccines are approved to treat or prevent filovirus infections. In this review, we examine the current treatments available to administer care for filovirus infection, the potential therapeutic targets that can be used for filovirus drug development, and the various drug targeting techniques used against filoviruses.

Human cytomegalovirus (HCMV) infections are usually benign and self-limiting in the immunocompetent population; however, HCMV is a well-recognized problem among immunocompromised patients (in particular immunosuppressed patients with stem cell or solid organ transplantation, AIDS, or cancer). In this group of patients, HCMV infections are a significant cause of morbidity and mortality. Additionally, congenital HCMV infections are a leading cause of birth defects and infections in children, occurring in 1 to 2% of all live births. Currently available drugs for the treatment of HCMV diseases in the immunocompromised host include ganciclovir (GCV), its oral prodrug valganciclovir (VGCV), cidofovir (CDV), foscavir (FOS), and fomivirsen. Except for fomivirsen, all these drugs are targeted at the viral DNA polymerase. Even if presently approved anti-HCMV drugs have considerable helped in the management of HCMV disease in the immunocompromised host, their use is limited due to questions of toxicity, poor oral bioavailability, modest efficacy, and development of virus-drug resistance. Furthermore, no drug has been licensed to treat congenital HCMV. For these reasons, there is a real need to develop new compounds active against HCMV. The search for novel inhibitors of HCMV replication has led to the identification of new molecular viral targets such as the protein kinase UL97 and proteins involved in genome replication or in viral maturation and egress. Moreover, a new strategy based on the identification of specific cellular targets required for viral replication has been developed. This review will focus on new compounds that inhibit a specific viral process (viral targets) and on cell-based approaches (cellular targets) that result in selective inhibition of virus replication.

Coronaviruses are important human and animal pathogens of the order Nidovirales. Several new members were discovered following the emergence of SARS-CoV in human populations, including two human coronaviruses and several animal coronaviruses. They cause respiratory and gastrointestinal illnesses and have been found in the brains of patients with multiple sclerosis. The high mortality of SARS, the identification of a natural reservoir, and the well-founded fear of provoking antibody-enhanced disease as a result of vaccination fueled the ongoing efforts in anti-coronavirus drug discovery. This review presents the results of current research.