Recent advances in antiviral agents: antiviral drug discovery for hepatitis viruses

Hepatitis B virus (HBV)- or hepatitis C virus (HCV)- associated liver diseases are now one of the important health problems in the world because of the high numbers of patients and the serious consequences. Recently, however, relatively effective treatments with antiviral agents have become available. Interferon (IFN), lamivudine and adefovir are now approved for treatment of HBV-associated liver diseases and they have been shown to be fairly effective. The goal of treatments for HBV-associated liver disease is to achieve a clinical cure in as short a period as possible without producing resistance mutation of the virus. Several nucleotide analogues with more potent antiviral activities are now in clinical trials. In the case of HCV-associated liver diseases, Pegylated IFN (Peg IFN) + ribavirin combination therapy is the standard and most effective treatment with a sustained response of 60-70%. The goal of the treatments for these liver diseases is to induce the complete eradication of the infected virus and at present new anti HCV drugs targeting the molecular segments of the virus are under development. It is expected that the complete eradication of infected virus will be possible in most cases in the near future.     

Glycosyltransferases, important tools for drug design

An increasing appreciation of carbohydrates as components of natural products has uncovered new opportunities in carbohydrate-based drug design. Glycosylated natural products produced by microorganisms contain a variety of different sugars. Usually the biosynthetic pathways to deoxysugars start from a monosacchride-1-phosphate which is converted to a NDP-hexose by a nucleotidyltransferase. Modification of this intermediate by different enzymes (e.g. dehydratases, epimerases, aminotransferases) yields the final sugar. In contrast to microorganisms, plant products mostly contain glucose, galactose, rhamnose and xylose as structural elements. In all organisms the nucleotide-activated sugar is attached to an aglycon by a glycosyltransferrase (GT). As no single universal GT has been uncovered yet, accomplishing the generation of novel glycosylated compounds requires a deep understanding of the function of glycosyltransferases (GTs) and its specificity. In this review we will present important drugs that contain sugar components. We will give an overview about the existing natural product GTs and we will discuss the structural features of GTs. Through specific examples within different compound classes, we will highlight recent examples of metabolic and combinatorial engineering approaches successfully applied to the production of novel glycosylated compounds.     

药物分子设计的策略：论药效团和骨架迁越

药物分子是由药效团和结构骨架构成的，药效团是由不连续的离散的原子、基团或片断所构成，但需结合在分子骨架上，形成具体的分子。骨架具有连续性，相同的药效团附着在不同的分子骨架上，构成了作用于同一靶标而结构多样的化合物。骨架依据受体的柔性和可塑性形成了“杂乱性”的空间。显示了受体结合部位的杂乱性。杂乱性越大，可容纳的配体分子的结构多样性就越多，意味着结构修饰与变换的余地大，成药的机会多。由苗头化合物演化成先导物，进而优化成候选药物，这由化合物变革成安全、有效、稳定、可控的药物过程就是保持药效团、变换分子骨架、修饰基团和边链的过程。结构骨架的变化可分为3个层次：以电子等排原理变换骨架结构；以优势结构为导向变换骨架结构；以结构一活性演化的方式变换骨架结构，即骨架迁越。骨架迁越的目的是改善分子的物化、药代、稳定性和赋予分子的结构新颖性。该文以实例阐述了骨架变换的方法与技巧。     

Closing the door on flaviviruses: entry as a target for antiviral drug design

With the emergence and rapid spread of West Nile virus in the United States since 1999, and the 50-100 million infections per year caused by dengue virus globally, the threat of flaviviruses as re-emerging human pathogens has become a reality. To support the efforts that are currently being pursued to develop effective vaccines against these viruses, researchers are also actively pursuing the development of small molecule compounds that target various aspects of the virus life cycle. Recent advances in the structural characterization of the flaviviruses have provided a strong foundation towards these efforts. These studies have provided the pseudo-atomic structures of virions from several members of the genus as well as atomic resolution structures of several viral proteins. Most importantly, these studies have highlighted specific structural rearrangements that occur within the virion that are necessary for the virus to complete its life cycle. These rearrangements occur when the virus must transition from immature, to mature, to fusion-active states and rely heavily on the conformational flexibility of the envelope (E) protein that forms the outer glycoprotein shell of the virus. Analysis of these conformational changes can suggest promising targets for structure-based antiviral design. For instance, by targeting the flexibility of the E protein, it might be possible to inhibit required rearrangements of this protein and trap the virus in a specific state. This would interfere with a productive flaviviral infection. This review presents a structural perspective of the flavivirus life cycle and focuses on the role of the E protein as an opportune target for structure-based antiviral drug design.     

The implications of resistance to antiviral agents for herpesvirus drug targets and drug therapy.

Antiviral drug resistance is an area of increasing clinical importance in treatment of a number of viruses including herpes simplex virus (HSV) and human cytomegalovirus (CMV). Work with these herpesviruses illustrates the value of studies of drug resistance. Novel aspects of drug mechanisms, such as a CMV gene product that contributes to ganciclovir phosphorylation, can be identified via drug resistance mutations. Drug targets such as the HSV DNA polymerase that are involved in drug recognition can be dissected by sequencing of drug-resistance mutations, which can point to alternate therapeutic strategies. Analysis of virus mutants in animal models and in patient populations can help assess the value of viral proteins such as the HSV thymidine kinase and ribonucleotide reductase as drug targets and the pathogenic potential of drug resistant mutants. Such studies reveal a broad spectrum of alterations conferring resistance and emphasize the importance of heterogeneous populations of virus in resistance and pathogenesis and the need to develop alternate therapies.     

Ion channels as important targets for antiepileptic drug design

Ion channels have a critical role in the function of the nervous system, where they instigate and conduct nerve impulses by asserting control over the voltage potential across the plasma membrane. Propagation of electrical impulses occurs by opening of voltage-gated ion channels. Ion channel blockers prevent this from occurring, and can therefore be used in the treatment of central nervous system disorders and neuropathic pain. Recent identification of ion channel gene mutations in Mendelian epilepsies suggests that genetically driven neuronal hyperexcitability plays an important role in epileptogenesis. Studies with animal seizure models have indicated that changes in temporal and spatial expression of voltage-gated sodium channels may be important in the pathology of epilepsy. This paper is aimed at elucidating the organization of the ion channels and covers a review on the antiepileptic drugs, both established and currently under development targeted to the ion channels in order to bring about effective seizure control.     

Computer-aided drug design methodologies toward the design of anti-hepatitis C agents

Hepatitis C constitutes an infectious disease that causes severe damages to the liver, and is caused by hepatitis C virus. There is no vaccine against this type of disease and the number of people infected continues to grow worldwide. The anti-viral therapy which is currently used is a mixture of interferon alpha-2a with ribavirin, but approximately half of the patients do not respond to therapy. Therefore, it is necessary to search for new compounds with anti-hepatitis C activity. Computer-aided drug design methodologies have been vital in the discovery of candidates to drugs. This review is dedicated to the role of computer-aided drug design methodologies for the development of new anti-hepatitis C agents. In addition, we introduce a QSAR model based on substructural approaches in order to model the anti-hepatitis C activity in vivo.     

AVCpred: an integrated web server for prediction and design of antiviral compounds

Viral infections constantly jeopardize the global public health due to lack of effective antiviral therapeutics. Therefore, there is an imperative need to speed up the drug discovery process to identify novel and efficient drug candidates. In this study, we have developed quantitative structure–activity relationship (QSAR)‐based models for predicting antiviral compounds (AVCs) against deadly viruses like human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), human herpesvirus (HHV) and 26 others using publicly available experimental data from the ChEMBL bioactivity database. Support vector machine (SVM) models achieved a maximum Pearson correlation coefficient of 0.72, 0.74, 0.66, 0.68, and 0.71 in regression mode and a maximum Matthew's correlation coefficient 0.91, 0.93, 0.70, 0.89, and 0.71, respectively, in classification mode during 10‐fold cross‐validation. Furthermore, similar performance was observed on the independent validation sets. We have integrated these models in the AVCpred web server, freely available at http://crdd.osdd.net/servers/avcpred . In addition, the datasets are provided in a searchable format. We hope this web server will assist researchers in the identification of potential antiviral agents. It would also save time and cost by prioritizing new drugs against viruses before their synthesis and experimental testing.     

Phosphorodiamidates as a promising new phosphate prodrug motif for antiviral drug discovery: application to anti-HCV agents

We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2'-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both d and l, and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 μM, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases.     

The need for new antiviral agents

Population density and immune status, vectors and virulence of infection, nutritional status, sanitation, genetic susceptibility and medical management of cases, are important factors influencing the incidence and/or severity of virus infections. Thus, the prevalence and clinical importance of virus infections and the need for antiviral drugs differ from place to place and from time to time. National and World Health Statistics of notifications of disease give some index of the incidence of infections but not all virus infections are notifiable. Such statistics can be misleading also through failures to notify from sloth on the part of the physician or, in the absence of pathognomonic symptoms or signs, from errors in diagnosis. Any assessment of the need for new antiviral drugs should consider the availability, safety, effectiveness and cost of alternative measures, including prevention of spread of infection by control of vectors, immunization by use of viral vaccines, or treatment with existing antiviral drugs. Early start of treatment of acute virus infections with existing drugs gives the best results and, where the clinical diagnosis is uncertain, accurate rapid virus diagnosis is of paramount importance. Many virus infections are asymptomatic or of trivial importance and without sequelae. However, new or improved antiviral drugs are needed for the prevention and/or treatment of a number of significant conditions caused by viruses which are not at present adequately controlled. These include upper and lower respiratory tract infections, influenza, chronic hepatitis, gastroenteritis, infectious mononucleosis, measles, rabies, haemorrhagic fevers and warts. Furthermore, such drugs might prove of therapeutic value in the prevention or treatment of virus-associated tumours, such as hepatoma, nasopharyngeal carcinoma, Burkitt's lymphoma, Kaposi's sarcoma and possibly carcinoma of the cervix.     

Microbial biotransformation – an important tool for the study of drug metabolism

1. Metabolite identification is an integral part of both preclinical and clinical drug discovery and development. Synthesis of drug metabolites is often required to support definitive identification, preclinical safety studies and clinical trials.

2. Here we describe the use of microbial biotransformation as a tool to produce drug metabolites, complementing traditional chemical synthesis and other biosynthetic methods such as hepatocytes, liver microsomes and recombinant human drug metabolizing enzymes.

3. A workflow is discussed whereby microbial strains are initially screened for their ability to form the putative metabolites of interest, followed by a scale-up to afford quantities sufficient to perform definitive identification and further studies.

4. Examples of the microbial synthesis of several difficult-to-synthesize hydroxylated metabolites and three difficult-to-synthesize glucuronidated metabolites are described, and the use of microbial biotransformation in drug discovery and development is discussed.

     

Orthopoxvirus targets for the development of new antiviral agents

Investments in the development of new drugs for orthopoxvirus infections have fostered new avenues of research, provided an improved understanding of orthopoxvirus biology and yielded new therapies that are currently progressing through clinical trials. These broad-based efforts have also resulted in the identification of new inhibitors of orthopoxvirus replication that target many different stages of viral replication cycle. This review will discuss progress in the development of new anti-poxvirus drugs and the identification of new molecular targets that can be exploited for the development of new inhibitors. The prototype of the orthopoxvirus group is vaccinia virus and its replication cycle will be discussed in detail noting specific viral functions and their associated gene products that have the potential to serve as new targets for drug development. Progress that has been achieved in recent years should yield new drugs for the treatment of these infections and might also reveal new approaches for antiviral drug development with other viruses.     

New antiviral agents for the treatment of hepatitis C: ABT-450

In pulmonary medicine, there are two major international meetings held annually: the annual meeting of the American Thoracic Society (ATS), and that of the European Respiratory Society (ERS). The 2006 ERS Annual Congress was held in Munich, Germany. Both meetings provide an annual forum for scientists and clinical investigators from academia, non-university institutions (including private practices) and pharmaceutical companies to share information on many aspects of pulmonary and critical-care medicine, sleep disorders, pulmonary infectious diseases, malignancies of the chest, and numerous aspects of diagnostic and interventional procedures in these fields. With > 5000 abstracts and ~ 17,000 participants, the 2006 ERS-congress outnumbered even the 2006 ATS meeting. Research areas covered all aspects of pulmonary diseases, although this year (as in previous years) obstructive pulmonary diseases such as COPD (chronic obstructive pulmonary disease) and asthma were clearly the main focus.