Current drug targets. Infectious disorders最新文献

Neuraminidase inhibitors as antiviral agents. 神经氨酸酶抑制剂作为抗病毒药物。

Current drug targets. Infectious disorders Pub Date : 2005-12-01 DOI: 10.2174/156800505774912884

I V Alymova, G Taylor, A Portner

{"title":"Neuraminidase inhibitors as antiviral agents.","authors":"I V Alymova, G Taylor, A Portner","doi":"10.2174/156800505774912884","DOIUrl":"https://doi.org/10.2174/156800505774912884","url":null,"abstract":"The enzyme neuraminidase (NA) is an attractive target for antiviral strategy because of its essential role in the pathogenicity of many respiratory viruses. NA removes sialic acid from the surface of infected cells and virus particles, thereby preventing viral self-aggregation and promoting efficient viral spread; NA also plays a role in the initial penetration of the mucosal lining of the respiratory tract. Random screening for inhibitors has identified only low-affinity and nonselective viral NA inhibitors. Selective, high-affinity inhibitors of influenza virus neuraminidase, zanamivir and oseltamivir, were developed using computer-aided design techniques on the basis of the three-dimensional structure of the influenza virus NA. These drugs were highly efficient in inhibiting replication of both influenza A and B viruses in vitro and in vivo and were approved for human use in 1999. Subsequently, the same structure-based design approach was used for the rational design of inhibitors of the parainfluenza virus hemagglutinin-neuraminidase (HN). One of these compounds, BCX 2798, effectively inhibited NA activity, cell binding, and growth of parainfluenza viruses in tissue culture and in the lungs of infected mice. Clinical reports indicate high efficiency of NA inhibitors for prophylaxis and treatment of influenza virus infection, good tolerance, and a low rate of emergence of drug-resistant mutants. Future experimental and clinical studies should establish the viability of NA inhibitors for the treatment of other respiratory virus infections.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 4","pages":"401-9"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800505774912884","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25904643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 32

Developments in antiviral drug design, discovery and development in 2004. 2004年抗病毒药物的设计、发现和开发进展。

Current drug targets. Infectious disorders Pub Date : 2005-12-01 DOI: 10.2174/156800505774912893

Nicholas A Meanwell, Makonen Belema, David J Carini, Stanley V D'Andrea, John F Kadow, Mark Krystal, B Narasimhulu Naidu, Alicia Regueiro-Ren, Paul M Scola, Sing-Yuen Sit, Michael A Walker, Tao Wang, Kap-Sun Yeung

引用次数: 5

Chemosensitizers in drug transport mechanisms involved in protozoan resistance. 药物转运机制中的化学增敏剂与原生动物耐药性有关。

Current drug targets. Infectious disorders Pub Date : 2005-12-01 DOI: 10.2174/156800505774912875

Bruno Pradines, Jean-Marie Pagès, Jacques Barbe

{"title":"Chemosensitizers in drug transport mechanisms involved in protozoan resistance.","authors":"Bruno Pradines, Jean-Marie Pagès, Jacques Barbe","doi":"10.2174/156800505774912875","DOIUrl":"https://doi.org/10.2174/156800505774912875","url":null,"abstract":"The emergence and spread of antiparasitic drug resistance pose a severe and increasing public health threat. Failures in prophylaxis or those in treatment with quinolines, hydroxynaphtoquinones, sesquiterpenic lactones, antifolate drugs, arsenic and antimony containing drugs sulfamides induce reemergence of parasitic-related morbidity and mortality. Resistance is often associated with alteration of drug accumulation into parasites, which results from a reduced uptake of the drug, an increased efflux or, a combination of the two processes. Resistance to quinolines, artemisinin derivatives and arsenicals and expression of an active efflux mechanism are more or less correlated in protozoa like Plasmodium spp., Leishmania spp., and Trypanosoma spp. Various parasite candidate genes have been proposed to be involved in drug resistance, each concerned in membrane transport. Genes encoding membrane glycoproteins, orthologue to the P-glycoproteins identified in MDR human cancer cells, have been described in these resistant pathogens in addition to various membrane proteins involved in drug transport. Several compounds have demonstrated, in the past decade, promising capability to reverse the drug resistance in parasite isolates in vitro, in animal models and for human malaria. These drugs belong to different pharmacological classes such as calcium channel blockers, tricyclic antidepressants, antipsychotic calmodulin antagonists, histamine H1-receptor antagonists, analgesic antipyretic drugs, non-steroidal anti-inflammatory drugs, and to different chemical classes such as synthetic surfactants, alkaloids from plants used in traditional medicine, pyrrolidinoaminoalkanes and derivatives, and anthracene derivatives. Here, are summarized the molecular bases of antiparasitic resistance emphasizing recent developments with compounds acting on trans-membrane proteins involved in drug efflux or uptake.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 4","pages":"411-31"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800505774912875","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25904644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 24

Discoveries of Tat-TAR interaction inhibitors for HIV-1. HIV-1的Tat-TAR相互作用抑制剂的发现。

Current drug targets. Infectious disorders Pub Date : 2005-12-01 DOI: 10.2174/156800505774912901

Ming Yang

{"title":"Discoveries of Tat-TAR interaction inhibitors for HIV-1.","authors":"Ming Yang","doi":"10.2174/156800505774912901","DOIUrl":"https://doi.org/10.2174/156800505774912901","url":null,"abstract":"A major problem associated with anti-HIV-1 treatment is rapid emergence of drug-resistant strains. Accordingly, a compelling need is to discover anti-HIV drugs against alternative viral targets in addition to HIV-1 RT, PR, IN and CCR5. One such target is the interaction between HIV Trans-activator of transcription (Tat) protein and Trans Activation Responsive region (TAR) RNA. An arginine-rich motif (ARM) of Tat recognizing both the base sequence and the active conformation of TAR RNA three-base bulge region as well as newly elucidated TAR RNA inactive conformation are important for the specific Tat-TAR interaction. According to the possible binding modes, the inhibitors have been mainly divided into two classes: (1) Compounds binding directly to TAR RNA either to the TAR RNA three-base bulge region alone or to the three-base bulge together with the lower and upper-stem/Loop region. (2) Compounds binding directly to Tat protein with high affinity, thus potently inhibiting HIV-1. They both block Tat trans-activation in the formation of the Tat/TAR complex to exert antiviral activity in primary human cells. Recent researches also focus on the drugs targeting specificity of Tat and TAR by such new assays as capillary electrophoresis and quartz crystal microbalance. Cell-based reporter systems are established for high-throughput screening of novel compounds that interfere with Tat transactivation. The identification of dominant-negative mutants also finds wide application in this field. The Tat-TAR interaction is an important target in efforts to develop anti-HIV gene therapy or potential therapeutic antiviral agents for the treatment of HIV-1 infections.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 4","pages":"433-44"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800505774912901","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25905072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 42

Combination antifungal therapy for invasive aspergillosis: utilizing new targeting strategies. 侵袭性曲霉病的联合抗真菌治疗:利用新的靶向策略。

Current drug targets. Infectious disorders Pub Date : 2005-09-01 DOI: 10.2174/1568005054880145

William J Steinbach

引用次数: 19

Dendrimers and antivirals: a review. 树状大分子与抗病毒药物综述。

Current drug targets. Infectious disorders Pub Date : 2005-09-01 DOI: 10.2174/1568005054880127

A Rosa Borges, C-L Schengrund

{"title":"Dendrimers and antivirals: a review.","authors":"A Rosa Borges, C-L Schengrund","doi":"10.2174/1568005054880127","DOIUrl":"https://doi.org/10.2174/1568005054880127","url":null,"abstract":"In response to the need for antiviral agents, dendrimers, hyper-branched, well-defined, and chemically versatile molecules, have been found to have a number of potential uses. How they are used is based on knowledge of 1) how a virus interacts with its target cells, 2) how it replicates, and 3) which viral components are recognized by the immune response of the host. Many viral-host cell interactions are initiated by viral proteins binding to specific cell surface carbohydrates. Dendrimers offer an efficient means of presenting multiple ligands, or sites of contact, on a single molecule. Derivatized with carbohydrate residues, the multivalent ligands have been shown to inhibit viral binding. Dendrimers derivatized with peptides or anionic groups have also been found to inhibit infection. The availability of a number of different types of dendrimers permits synthesis of potential inhibitors of viral binding to be tailored to meet the dimensions needed for optimum adherence by the virus. Future directions should see increased studies of the use of dendrimers as carriers of 1) multiple indicators on a viral probe to increase diagnostic sensitivity, 2) multiple peptides for use as immunogens or as inhibitors of viral binding, and 3) inhibitors of viral enzymes. While the field of dendrimer chemistry is relatively young, promising results indicate that dendrimers may provide the scaffolding needed for development of effective antivirals.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 3","pages":"247-54"},"PeriodicalIF":0.0,"publicationDate":"2005-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054880127","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25599964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 61

The molecular basis for the mode of action of bicyclomycin. 双环霉素作用方式的分子基础。

Current drug targets. Infectious disorders Pub Date : 2005-09-01 DOI: 10.2174/1568005054880136

Harold Kohn, William Widger

{"title":"The molecular basis for the mode of action of bicyclomycin.","authors":"Harold Kohn, William Widger","doi":"10.2174/1568005054880136","DOIUrl":"https://doi.org/10.2174/1568005054880136","url":null,"abstract":"Bicyclomycin (1) is a clinically useful antibiotic exhibiting activity against a broad spectrum of Gram-negative bacteria and against the Gram-positive bacterium, Micrococcus luteus. Bicyclomycin has been used to treat diarrhea in humans and bacterial diarrhea in calves and pigs and is marketed by Fujisawa (Osaka, Japan) under the trade name Bicozamycin. The structure of 1 is unique among antibiotics, and our studies document that its mechanism of action is novel. Early mechanistic proposals suggested that 1 reacted with nucleophiles (e.g., a protein sulfhydryl group) necessary for the remodeling the peptidoglycan assembly within the bacterial cell wall. We, however, showed that 1 targeted the rho transcription termination factor in Escherichia coli. The rho protein is integral to the expression of many gene products in E. coli and other Gram-negative bacteria, and without rho the cell losses viability. Rho is a member of the RecA-type ATPase class of enzymes that use nucleotide contacts to couple oligonucleotide translocation to ATP hydrolysis. Bicyclomycin is the only known selective inhibitor of rho. In this article, we integrate the evidence obtained from bicyclomycin structure-activity studies, site-directed mutagenesis investigations, bicyclomycin affinity labels, and biochemical and biophysical measurements with recent X-ray crystallographic images of the bicyclomycin-rho complex to define the rho antibiotic binding site and to document the pathway for rho inhibition by 1. Together, the structural and functional studies demonstrate how 1, a modest rho inhibitor, can disrupt the rho molecular machinery thereby leading to a catastrophic effect caused by the untimely overproduction of proteins not normally expressed constitutively, thus leading to a toxic effect on the cells.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 3","pages":"273-95"},"PeriodicalIF":0.0,"publicationDate":"2005-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054880136","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25599967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 56

Identification of inhibitors of bacterial enoyl-acyl carrier protein reductase. 细菌烯酰酰基载体蛋白还原酶抑制剂的鉴定。

Current drug targets. Infectious disorders Pub Date : 2005-09-01 DOI: 10.2174/1568005054880154

Donald T Moir

{"title":"Identification of inhibitors of bacterial enoyl-acyl carrier protein reductase.","authors":"Donald T Moir","doi":"10.2174/1568005054880154","DOIUrl":"https://doi.org/10.2174/1568005054880154","url":null,"abstract":"The FabI-related enoyl-ACP reductase enzymes of bacteria meet many of the criteria for antibacterial targets. These enzymes are essential for the growth of several pathogenic species, have no significant mammalian homologs, catalyze a rate-limiting step in a vital macromolecular biosynthetic pathway, and are already the targets of antibacterials used in the clinic (isoniazid) and in consumer products (triclosan). The suitability of FabI as an antibiotic target is diminished somewhat by the discovery that many pathogens carry an alternate unrelated enoyl-ACP reductase (FabK) or both reductases. However, a key human pathogen, Staphylococcus aureus and its increasingly common drug-resistant derivative MRSA are sensitive to FabI inhibitors. Screening for inhibitors of this target has resulted in the identification of five chemical classes of potent inhibitors. In addition, analogs of triclosan with increased potency and with pro-drug features have been engineered. At least one of these classes of inhibitors has been optimized and tested in animals for pharmacokinetic properties and efficacy. Further development of one or more of these classes and further screening are expected to generate new FabI inhibitors for application in the clinic against drug-resistant S. aureus.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 3","pages":"297-305"},"PeriodicalIF":0.0,"publicationDate":"2005-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054880154","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25599968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 41

Quinolone-based drugs against Toxoplasma gondii and Plasmodium spp. 喹诺酮类药物抗刚地弓形虫和疟原虫。

Current drug targets. Infectious disorders Pub Date : 2005-09-01 DOI: 10.2174/1568005054880172

Guillaume Anquetin, Jacques Greiner, Pierre Vierling

{"title":"Quinolone-based drugs against Toxoplasma gondii and Plasmodium spp.","authors":"Guillaume Anquetin, Jacques Greiner, Pierre Vierling","doi":"10.2174/1568005054880172","DOIUrl":"https://doi.org/10.2174/1568005054880172","url":null,"abstract":"Owing to the rapid emergence of multi-resistant strains of Plasmodium spp. (the causative agents of malaria) and the limitations of drugs used against Toxoplasma gondii (an important opportunistic pathogen associated with AIDS and congenital birth defects), the discovery of new therapeutical targets and the development of new drugs are needed. The presence of the prokaryotic-like organelle in apicomplexan parasites (i.e. plastids), which comprise these major human pathogens, may represent a unique target for antibiotics against these protozoa. Quinolones which are known to be highly potent against bacteria were also found to specifically disrupt these parasites. They inhibit DNA replication by interacting with two essential bacterial type II topoisomerases, DNA gyrase and topoisomerase IV. There are some clues that quinolones act on plastids with a similar mechanism of action. After a brief presentation of plasmodium and toxoplasma dedicated to their life cycle, the chemotherapies presently used in clinics to fight against these protozoa and the potential new targets and drugs, we will focus our attention on their plastid which is one of these promising new targets. Then, we will present the various drugs and generations of quinolones, the leading molecules, and their inhibitory effects against these parasites together with their pharmacological properties that have been established from in vitro and in vivo studies. We will also discuss their possible mode of action.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 3","pages":"227-45"},"PeriodicalIF":0.0,"publicationDate":"2005-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054880172","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25599963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 20

Mechanisms of drug resistance in Mycoplasma pneumoniae. 肺炎支原体的耐药机制。

Current drug targets. Infectious disorders Pub Date : 2005-09-01 DOI: 10.2174/1568005054880109

C M Bébéar, S Pereyre

{"title":"Mechanisms of drug resistance in Mycoplasma pneumoniae.","authors":"C M Bébéar, S Pereyre","doi":"10.2174/1568005054880109","DOIUrl":"https://doi.org/10.2174/1568005054880109","url":null,"abstract":"Mycoplasma pneumoniae is a pathogenic mycoplasma responsible for respiratory tract infections in humans, occurring worldwide in children and adults. This review briefly focuses on its antibiotic susceptibility profile and on the development of acquired resistance for this microorganism. The lack of a cell wall in mycoplasmas makes them intrinsically resistant to beta-lactams and to all antimicrobials which target the cell wall. Intrinsic resistance related to specific mycoplasma species concerns essentially the acrolide-lincosamide-streptogramin-ketolide (MLSK) antibiotic group. M. pneumoniae is susceptible to all MLSK antibiotics, except to lincomycin. Among the three antibiotic classes used for the treatment of mycoplasmal infections including tetracyclines, MLSK group, and fluoroquinolones, macrolides and related antibiotics are the drug of choice for respiratory infections caused by M. pneumoniae. Both target alterations and efflux mechanisms implicated in acquired antibiotic resistance have been described in mycoplasmas either by genetic mutation or transfer of new genes carried by transposons. At present, M. pneumoniae remains greatly susceptible to antibiotics, but as this mycoplasma is difficult to isolate, the number of clinical strains tested is limited and the occurrence of acquired resistance not well documented. However some strains having acquired resistance to MLSK have been decribed in vivo and erythromycin-resistant isolates are spreading now in Japan. To date, no clinical isolates resistant to fluoroquinolones or tetracyclines have been described in the literature, but some strains having acquired resistance to both classes have been selected in vitro. Molecular diagnosis of this acquired resistance has been related to target alterations, in ribosome for macrolides and tetracyclines, or in topoisomerase II genes for fluoroquinolones.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 3","pages":"263-71"},"PeriodicalIF":0.0,"publicationDate":"2005-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054880109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25599966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 66