Current drug targets. Infectious disorders最新文献_第6页

Determining and overcoming resistance to HIV protease inhibitors. 确定和克服对HIV蛋白酶抑制剂的耐药性。

Current drug targets. Infectious disorders Pub Date : 2004-06-01 DOI: 10.2174/1568005043340984

Jana Prejdová, Milan Soucek, Jan Konvalinka

{"title":"Determining and overcoming resistance to HIV protease inhibitors.","authors":"Jana Prejdová, Milan Soucek, Jan Konvalinka","doi":"10.2174/1568005043340984","DOIUrl":"https://doi.org/10.2174/1568005043340984","url":null,"abstract":"HIV protease represents a major target for development of antiviral therapeutics. The introduction of HIV protease (PR) inhibitors (PIs) to clinical practice and the application of highly active antiretroviral therapy resulted in decreased mortality and prolonged life expectancy of HIV-positive patients. However, the high polymorphism of HIV leads to rapid selection of viral variants resistant towards the inhibitors. Such resistant PR variants have developed in HIV-positive patients after treatment with any of the eight PIs approved for clinical use. In this review we overview (i) the methods for the identification and assessment of viral resistance in HIV positive patients, and (ii) the approaches medicinal chemists take to overcome it. Rational antiviral therapy brings about the need for quantitative assessment of the level of drug resistance development in the course of the treatment. At present, two main approaches are taken: in genotypic assays the viral sequences are PCR amplified, sequenced and changes in the viral gene sequence known to be associated with reduced drug sensitivity are identified, while phenotypic assays test the ability of a virus to grow in the presence of a drug or combination of drugs. The advantages and drawbacks of these methods, as well as their relevance for the therapy are discussed. We also review the efforts to design second-generation PIs, capable of potently inhibiting multi-resistant HIV-1 PR species, using structure-assisted design of the compounds targeted to the active site, as well as alternative approaches with compounds binding to other domains of the PR molecule.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"4 2","pages":"137-52"},"PeriodicalIF":0.0,"publicationDate":"2004-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24552420","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

Candida and candidiasis: the cell wall as a potential molecular target for antifungal therapy. 念珠菌和念珠菌病:细胞壁作为抗真菌治疗的潜在分子靶点。

Current drug targets. Infectious disorders Pub Date : 2004-06-01 DOI: 10.2174/1568005043341046

Daniel Gozalbo, Patricia Roig, Eva Villamón, María Luisa Gil

{"title":"Candida and candidiasis: the cell wall as a potential molecular target for antifungal therapy.","authors":"Daniel Gozalbo, Patricia Roig, Eva Villamón, María Luisa Gil","doi":"10.2174/1568005043341046","DOIUrl":"https://doi.org/10.2174/1568005043341046","url":null,"abstract":"The fungal species Candida albicans is an opportunistic pathogen, which causes serious infections in humans, particularly in immunocompromised patients. Depending on the underlying host defect, C. albicans causes a variety of infections, ranging from superficial mucocutaneous candidiasis to life-threatening disseminated infections. Both the limited spectrum of antifungal drugs currently in clinical use and the emergence of resistances make necessary the development of new effective antifungal drugs with minimal side effects; however, such a research is limited by the small number of specific target sites identified to date. The cell wall is a fungal specific dynamic structure essential to almost every aspect of the biology and pathogenicity of C. albicans. Its structure confers physical protection and shape to fungal cells, and as the most external part of the fungus, the cell wall mediates the interaction with the host, including adhesion to host tissues and modulation of the host anti-Candida immune response. Consequently, the fungal cell wall can be considered as a suitable target for development of new antifungal compounds. Therefore two distinct types of potential cell wall-related targets can be envisaged, according to their mode of action in inhibiting infection: (i) inhibition of cell wall biogenesis, which may impair cell wall integrity and thus cell viability, and (ii) modification of host-fungus interactions by inhibiting or blocking putative virulence factors, which may impair host colonization and progress of the infectious process. Antibodies specific to cell wall antigens may protect against infection by a variety of mechanisms and may evolve into save antifungal agents.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"4 2","pages":"117-35"},"PeriodicalIF":0.0,"publicationDate":"2004-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005043341046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24552419","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: 64

Novel tissue and cell type-specific gene/drug delivery system using surface engineered hepatitis B virus nano-particles. 利用表面工程B型肝炎病毒纳米颗粒的新型组织和细胞类型特异性基因/药物递送系统。

Current drug targets. Infectious disorders Pub Date : 2004-06-01 DOI: 10.2174/1568005043341037

Tadanori Yamada, Masakazu Ueda, Masaharu Seno, Akihiko Kondo, Katsuyuki Tanizawa, Shun'ichi Kuroda

引用次数: 19

Computer assisted searches for drug targets with emphasis on malarial proteases and their inhibitors. 以疟疾蛋白酶及其抑制剂为重点的药物靶点的计算机辅助搜索。

Current drug targets. Infectious disorders Pub Date : 2004-03-01 DOI: 10.2174/1568005043480952

Yufeng Wang, Yimin Wu

引用次数: 12

Proteomic approaches to studying drug targets and resistance in Plasmodium. 用蛋白质组学方法研究疟原虫的药物靶点和耐药性。

Current drug targets. Infectious disorders Pub Date : 2004-03-01 DOI: 10.2174/1568005043480989

R A Cooper, D J Carucci

{"title":"Proteomic approaches to studying drug targets and resistance in Plasmodium.","authors":"R A Cooper, D J Carucci","doi":"10.2174/1568005043480989","DOIUrl":"https://doi.org/10.2174/1568005043480989","url":null,"abstract":"Ever increasing drug resistance by Plasmodium falciparum, the most virulent of human malaria parasites, is creating new challenges in malaria chemotherapy. The entire genome sequences of P. falciparum and the rodent malaria parasite, P. yoelii yoelii are now available. Extensive genome sequence data from other Plasmodium species including another important human malaria parasite, P. vivax are also available. Powerful research techniques coupled to genomic resources are needed to help identify new drug and vaccine targets against malaria. Applied to Plasmodium, proteomics combines high-resolution protein or peptide separation with mass spectrometry and computer software to rapidly identify large numbers of proteins expressed from various stages of parasite development. Proteomic methods can be applied to study sub-cellular localization, cell function, organelle composition, changes in protein expression patterns in response to drug exposure, drug-protein binding and validation of data from genomic annotation and transcript expression studies. Recent high-throughput proteomic approaches have provided a wealth of protein expression data on P. falciparum, while smaller-scale studies examining specific drug-related hypotheses are also appearing. Of particular interest is the study of mechanisms of action and resistance of drugs such as the quinolines, whose targets currently may not be predictable from genomic data. Coupling the Plasmodium sequence data with bioinformatics, proteomics and RNA transcript expression profiling opens unprecedented opportunities for exploring new malaria control strategies. This review will focus on pharmacological research in malaria and other intracellular parasites using proteomic techniques, emphasizing resources and strategies available for Plasmodium.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"4 1","pages":"41-51"},"PeriodicalIF":0.0,"publicationDate":"2004-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005043480989","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40929743","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: 31

QTL analysis for discovery of genes involved in drug responses. QTL分析发现与药物反应相关的基因。

Current drug targets. Infectious disorders Pub Date : 2004-03-01 DOI: 10.2174/1568005043480916

Saunak Sen, Michael Ferdig

{"title":"QTL analysis for discovery of genes involved in drug responses.","authors":"Saunak Sen, Michael Ferdig","doi":"10.2174/1568005043480916","DOIUrl":"https://doi.org/10.2174/1568005043480916","url":null,"abstract":"The completed Plasmodium falciparum genome sequence poses a significant challenge: how do we bring this wealth of data to bear against the steady march of malaria parasites towards multiple-drug resistance? Studies of parasite drug resistance have until now focused on a qualitative, single-gene concept of resistance determination; however, the emergence of powerful genomics tools insists that these questions be rephrased. It is now possible to address the true genetic complexity underlying quantitative drug sensitivities. Quantitative trait loci (QTL) mapping is an effective tool for tracking multi-gene traits by partitioning genetic effects that influence these traits into specific genomic regions. A cross between two parasite clones captures allele combinations that have segregated into progeny clones that display varying sensitivity to drugs. The specific allele forms and their combinations contributed by each parent are, in effect, genetic signatures of their unique evolutionary histories. In addition to resistance genes, per se, a drug resistant parasite carries co-evolved gene combinations comprising a genetic background of drug resistance. Research into drug resistance necessarily has been directed at specific genes and mechanisms favored by a priori knowledge and assumptions about how resistance works. QTL mapping, by superimposing real biological phenotypes on genome sequence, structural polymorphisms, and gene expression data, can provide an alternative, unbiased view of the network of gene actions that build a complex phenotype. Through an integrated approach, studies can move beyond the search for markers of resistance to instead characterize the predisposition of parasites to develop new resistances and cross-resistances.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"4 1","pages":"53-63"},"PeriodicalIF":0.0,"publicationDate":"2004-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005043480916","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40929744","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: 18

Mapping drug resistance genes in Plasmodium falciparum by genome-wide association. 恶性疟原虫耐药基因全基因组关联图谱研究。

Current drug targets. Infectious disorders Pub Date : 2004-03-01 DOI: 10.2174/1568005043480943

Tim J C Anderson

{"title":"Mapping drug resistance genes in Plasmodium falciparum by genome-wide association.","authors":"Tim J C Anderson","doi":"10.2174/1568005043480943","DOIUrl":"https://doi.org/10.2174/1568005043480943","url":null,"abstract":"When alleles conferring drug resistance spread through a population of malaria parasites, they leave characteristic \"scars\" in the parasite genome. Flanking neutral polymorphisms \"hitchhike\" to high frequency with the resistance mutation, generating deep valleys of reduced variation and broad swathes of elevated linkage disequilibrium around the resistance locus. We can systematically search the genome for these scars by genotyping polymorphic marker loci at intervals throughout the genome of P. falciparum, and use them as signposts for locating drug resistance genes. In this review I outline the rational behind this approach to genetic mapping. I describe key features of P. falciparum population biology, such as recombination rate, inbreeding, and selection intensity that influence the size of genomic regions affected by selection and the choice of study population. I discuss suitable genetic markers, study designs, and statistical approaches to data analysis. Finally, to demonstrate the utility of the approach I describe two proof-of-principle studies documenting patterns of genetic variability around known drug resistance genes.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"4 1","pages":"65-78"},"PeriodicalIF":0.0,"publicationDate":"2004-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005043480943","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40929745","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: 64

Genetic and biochemical aspects of drug resistance in malaria parasites. 疟疾寄生虫耐药性的遗传和生化方面。

Current drug targets. Infectious disorders Pub Date : 2004-03-01 DOI: 10.2174/1568005043480925

K Hayton, X-z Su

{"title":"Genetic and biochemical aspects of drug resistance in malaria parasites.","authors":"K Hayton, X-z Su","doi":"10.2174/1568005043480925","DOIUrl":"https://doi.org/10.2174/1568005043480925","url":null,"abstract":"Drug resistance is one of the major factors contributing to the resurgence of malaria, especially resistance to the most affordable drugs such as chloroquine and Fansidar, a combination drug of pyrimethamine and sulfadoxine. Understanding the mechanisms of such resistance and developing new treatments, including new drugs, are urgently needed. Great progress has been made recently in studying the mechanisms of drug action and drug resistance in malaria parasites, particularly in Plasmodium falciparum. These efforts are highlighted by the demonstration of mutations in the parasite dihydrofolate reductase and dihydropteroate synthase genes conferring resistance to pyrimethamine and sulfadoxine, respectively, and by the recent discovery of mutations in the gene coding for a putative transporter, PfCRT, conferring resistance to chloroquine. Mutations in a homologue of a human multiple-drug-resistant gene, pfmdr1, have also been shown to be associated with responses to multiple drugs. However, except in the case of resistance to antifolate drugs, the mechanisms of action and resistance to most drugs currently in use are essentially unknown or are being debated. Additionally, novel mechanisms of resistance exist in different malaria parasites, complicating the process of developing new drugs and treatment strategies. Here we summarise the progress made in drug resistance research in malaria parasites over the past 20 years, emphasising the most recent developments in the genetics of drug resistance.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"4 1","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2004-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005043480925","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40851436","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: 83

Mitochondrial and plastid functions as antimalarial drug targets. 线粒体和质体作为抗疟药物靶点的功能。

Current drug targets. Infectious disorders Pub Date : 2004-03-01 DOI: 10.2174/1568005043480907

Akhil B Vaidya

{"title":"Mitochondrial and plastid functions as antimalarial drug targets.","authors":"Akhil B Vaidya","doi":"10.2174/1568005043480907","DOIUrl":"https://doi.org/10.2174/1568005043480907","url":null,"abstract":"Malaria parasites possess three genomes: the nuclear chromosomes, the mitochondrial genome, and the plastid genome. Realization that the parasites contain a plastid remnant with its own genome has created much excitement not only from a basic biological point of view but also from the prospects for developing new antimalarial drugs. Both the mitochondrial and the plastid genomes are the smallest examples of their kind known to date. The plastid appears to be derived from an ancestral secondary endosymbiotic event. Interestingly, the main functions usually associated with a mitochondrion and a plastid, i.e. oxidative phosphorylation and photosynthesis, do not appear to be conserved in malaria parasites. Completion of the parasite genome sequence has provided the opportunity to assess functions assigned to these highly derivatized organelles. It is clear that these organelles serve vital functions since interference with their activity is incompatible with parasite growth. A number of antimalarial compounds target functions of either the mitochondrion or the plastid. This review will survey our current understanding of mitochondrial and plastid functions with a view to identify processes that are or have a potential to be targets for antimalarial drugs.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"4 1","pages":"11-23"},"PeriodicalIF":0.0,"publicationDate":"2004-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005043480907","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40851437","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: 37

Targeting ion channels of Plasmodium falciparum-infected human erythrocytes for antimalarial development. 靶向恶性疟原虫感染的人红细胞的离子通道用于抗疟疾发展。

Current drug targets. Infectious disorders Pub Date : 2004-03-01 DOI: 10.2174/1568005043480934

Sanjay A Desai

引用次数: 0