Current drug targets. Infectious disorders最新文献_第7页

A review of HIV-1 resistance to the nucleoside and nucleotide inhibitors. HIV-1对核苷和核苷酸抑制剂的耐药性综述。

Current drug targets. Infectious disorders Pub Date : 2003-12-01 DOI: 10.2174/1568005033481024

Nancy Shulman, Mark Winters

{"title":"A review of HIV-1 resistance to the nucleoside and nucleotide inhibitors.","authors":"Nancy Shulman, Mark Winters","doi":"10.2174/1568005033481024","DOIUrl":"https://doi.org/10.2174/1568005033481024","url":null,"abstract":"The nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of agents used for the treatment of HIV and remain an important component of combination antiretroviral therapy. Resistance to the NRTIs occurs by the acquisition of mutations in the reverse transcriptase gene that result in a structural change that either decreases the NRTI incorporation into the extending nucleotide chain or enhances removal of the NRTI from the terminated chain, also known as primer unblocking or pyrophosphorylysis. There are several major genetic mutational patterns of resistance and cross-resistance that evolve with the NRTIs including the thymidine analog mutations M41L, D67N, K70R, L210W, T215Y, and K219Q/E/W, the non-thymidine mutations M184V, L74V, and K65R, and the multidrug resistant Q151M complex, as well as others. Increasing knowledge of resistance and cross-resistance patterns that evolve on the NRTIs as well as the other antiretroviral classes will help optimize antiretroviral treatment strategies. Advancing knowledge of the biochemical and structural basis of resistance will aid in the design of newer compounds that are active against HIV resistant to the currently available drugs, ultimately prolonging virologic suppression and life in the millions of people who are infected with HIV.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 4","pages":"273-81"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24188936","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: 27

Predicting the impact of antiretrovirals in resource-poor settings: preventing HIV infections whilst controlling drug resistance. 预测抗逆转录病毒药物在资源贫乏环境中的影响:在控制耐药性的同时预防艾滋病毒感染。

Current drug targets. Infectious disorders Pub Date : 2003-12-01 DOI: 10.2174/1568005033480999

Sally Blower, Li Ma, Paul Farmer, Serena Koenig

{"title":"Predicting the impact of antiretrovirals in resource-poor settings: preventing HIV infections whilst controlling drug resistance.","authors":"Sally Blower, Li Ma, Paul Farmer, Serena Koenig","doi":"10.2174/1568005033480999","DOIUrl":"https://doi.org/10.2174/1568005033480999","url":null,"abstract":"There is currently an opportunity to carefully plan the implementation of antiretroviral (ARV) therapy in the developing world. Here, we use mathematical models to predict the potential impact that low to moderate usage rates of ARVs might have in developing countries. We use our models to predict the relationship between the specific usage rate of ARVs (in terms of the percentage of those infected with HIV who receive such treatment) and: (i) the prevalence of drug-resistant HIV that will arise, (ii) the future transmission rate of drug-resistant strains of HIV, and (iii) the cumulative number of HIV infections that will be prevented through more widespread use of ARVs. We also review the current state of HIV/AIDS treatment programs in resource-poor settings and identify the essential elements of a successful treatment project, noting that one key element is integration with a strong prevention program. We apply both program experience from Haiti and Brazil and the insights gleaned from our modeling to address the emerging debate regarding the increased availability of ARVs in developing countries. Finally, we show how mathematical models can be used as tools for designing robust health policies for implementing ARVs in developing countries. Our results demonstrate that designing optimal ARV-based strategies to control HIV epidemics is extremely complex, as increasing ARV usage has both beneficial and detrimental epidemic-level effects. Control strategies should be based upon the overall impact on the epidemic and not simply upon the impact ARVs will have on the transmission and/or prevalence of ARV-resistant strains.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 4","pages":"345-53"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24188941","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: 78

Structural and thermodynamic basis of resistance to HIV-1 protease inhibition: implications for inhibitor design. 抵抗HIV-1蛋白酶抑制的结构和热力学基础:抑制剂设计的意义。

Current drug targets. Infectious disorders Pub Date : 2003-12-01 DOI: 10.2174/1568005033481051

Adrian Velazquez-Campoy, Salman Muzammil, Hiroyasu Ohtaka, Arne Schön, Sonia Vega, Ernesto Freire

{"title":"Structural and thermodynamic basis of resistance to HIV-1 protease inhibition: implications for inhibitor design.","authors":"Adrian Velazquez-Campoy, Salman Muzammil, Hiroyasu Ohtaka, Arne Schön, Sonia Vega, Ernesto Freire","doi":"10.2174/1568005033481051","DOIUrl":"https://doi.org/10.2174/1568005033481051","url":null,"abstract":"One of the most serious side effects associated with the therapy of HIV-1 infection is the appearance of viral strains that exhibit resistance to protease inhibitors. At the molecular level, resistance to protease inhibition predominantly takes the form of mutations within the protease molecule that preferentially lower the affinity of protease inhibitors with respect to protease substrates, while still maintaining a viable catalytic activity. Mutations associated with drug resistance occur within the active site cavity as well as distal sites. Active site mutations affect directly inhibitor/protease interactions while non-active site mutations affect inhibitor binding through long range cooperative perturbations. The effects of mutations associated with drug resistance are compounded by the presence of naturally occurring polymorphisms, especially those observed in non-B subtypes of HIV-1. The binding thermodynamics of all clinical inhibitors against the wild type protease, drug resistant mutations and non-B subtype HIV-1 proteases has been determined by high sensitivity isothermal titration calorimetry. In conjunction with structural information, these data have provided a precise characterization of the binding mechanism of different inhibitors and their response to mutations. Inhibitors that exhibit extremely high affinity and low susceptibility to the effects of mutations share common features and binding determinants even if they belong to different chemical scaffolds. These binding determinants define a set of rules and constraints for the design of better HIV-1 protease inhibitors.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 4","pages":"311-28"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24188939","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: 69

Is resistance futile? 抵抗是徒劳的吗?

Current drug targets. Infectious disorders Pub Date : 2003-12-01 DOI: 10.2174/1568005033481079

Victoria D Kutilek, Dennis A Sheeter, John H Elder, Bruce E Torbett

{"title":"Is resistance futile?","authors":"Victoria D Kutilek, Dennis A Sheeter, John H Elder, Bruce E Torbett","doi":"10.2174/1568005033481079","DOIUrl":"https://doi.org/10.2174/1568005033481079","url":null,"abstract":"A global effort has been undertaken to control human immunodeficiency virus (HIV) though the development of vaccines and pharmacologics. Current FDA approved pharmacological inhibitors target two of the three viral enzymes critical to replication and maturation of infectious viral particles: reverse transcriptase (RT) and protease (Pr). Although combination therapies targeting RT and Pr have significantly reduced AIDS related morbidity and mortality, resistance to individual inhibitors is a growing concern. Currently, there are six protease inhibitors in clinical use. These inhibitors target the active site of protease using peptidomimetic transition state analogs based on natural substrates. However, treatment failures arise as a lack of compliance due to HIV-inhibitor pharmacokinetics, toxicity, and tolerance. This allows reduced HIV-inhibitor pressure, increased viral replication, and the emergence of drug resistant mutations. Continued use of protease inhibitors in the face of incomplete viral suppression may result in HIV-1 escape mutants not only being resistant to the protease inhibitor used, but to all clinically available protease inhibitors. Thus, new broad-based protease inhibitors are needed to control the emerging multi-drug, cross-resistant HIV-1. Moreover, given the emergence of cross-resistant HIV-1, there is a need to target novel protease structural sites to reduce the risk of multi-drug cross-resistance. In this review, we discuss the resistance to protease inhibitors and the rationale for new strategies towards drug design for suppressing protease activity. We focus on the structure and function relationship and the influence that drug resistance mutants exert on the evolution of HIV-1 protease.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 4","pages":"295-309"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24188938","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

Mathematical approaches in the study of viral kinetics and drug resistance in HIV-1 infection. 用数学方法研究HIV-1感染的病毒动力学和耐药性。

Current drug targets. Infectious disorders Pub Date : 2003-12-01 DOI: 10.2174/1568005033481042

V Müller, S Bonhoeffer

{"title":"Mathematical approaches in the study of viral kinetics and drug resistance in HIV-1 infection.","authors":"V Müller, S Bonhoeffer","doi":"10.2174/1568005033481042","DOIUrl":"https://doi.org/10.2174/1568005033481042","url":null,"abstract":"We review some crucial aspects of drug therapy and viral resistance that have been investigated within the framework developed for the modelling of virus kinetics. First, we give a general overview on the use of mathematical models in the field of HIV research. We seek to identify the factors that determine the steady state virus load and show that stable reductions during antiviral therapy are difficult to explain within the standard model of virus dynamics. We discuss possible extensions that enable the models to account for the moderately reduced virus loads during non-suppressive treatment and argue that the residual viremia under suppressive treatment can probably be attributed to the survival of long-lived infected cells, rather than to new rounds of replication. Next, we address the emergence of resistance during suppressive therapy and demonstrate that the resistant virus is more likely to be present already at the start of treatment than to be generated during therapy. The appearance of resistance after a prolonged period of initial suppression indicates that drug efficacy is not continuously maintained over time. We investigate the potential risks and benefits of therapy interruptions. Considering the effect of recombination, we argue that it probably decelerates, rather than accelerates the evolution of multidrug-resistant virus. We also review state-of-the-art methods for the estimation of fitness, which is crucial to the understanding of the emergence of resistance during therapy or the re-emergence of wild type upon the cessation of therapy.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 4","pages":"329-44"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24188940","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: 10

Anti-HIV inhibitors based on nucleic acids: emergence of aptamers as potent antivirals. 基于核酸的抗hiv抑制剂:作为有效抗病毒药物的适体的出现。

Current drug targets. Infectious disorders Pub Date : 2003-12-01 DOI: 10.2174/1568005033481060

P J Joshi, T S Fisher, V R Prasad

{"title":"Anti-HIV inhibitors based on nucleic acids: emergence of aptamers as potent antivirals.","authors":"P J Joshi, T S Fisher, V R Prasad","doi":"10.2174/1568005033481060","DOIUrl":"https://doi.org/10.2174/1568005033481060","url":null,"abstract":"The development of resistance and the inability of currently approved antiretroviral drugs to completely eradicate HIV-1 have led to increased focus on therapies other than small molecules. Although nucleic acid-based intervention requires complex tasks involving intracellular delivery and/or stable expression in target cells, recent advances in gene therapy methods combined with continued progress in stem cell approaches have made nucleic acid-based compounds excellent candidates for effectively inhibiting intracellular targets. Consequently, multiple nucleic acid-based therapies are being developed. These include antisense nucleic acids, peptide nucleic acids and RNA decoys, which can interfere with HIV-1 replication. More recently, RNA interference, which exploits a novel cellular pathway, has been shown to effectively reduce viral titers in cell culture and promises to be a potential candidate for suppressing HIV replication in vivo. A promising candidate in the midst of these emerging approaches is the aptamer approach, which involves the use of a class of small nucleic acid molecules isolated from combinatorial libraries by an in vitro evolution protocol termed SELEX. Aptamers exhibit exquisite specificity, high affinity and the virtual lack of immunogenicity, features that make them exceptionally well-suited to combat HIV without affecting the host. The powerful nature of these specific antagonists of protein function could lead to the development of an effective anti-HIV therapy. Several highly specific, nucleic acid aptamers targeting select HIV proteins have been described. Investigations with anti-HIV RNA aptamers have shown an effective block to viral replication. This review summarizes the existing nucleic-acid based approaches to block HIV replication and attempts to chart the current progress in the development of aptamers against HIV, their use in inhibiting the virus replication, prospects for their use in the clinic and potential drawbacks.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 4","pages":"383-400"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24188786","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: 52

Resistance to HIV-1 entry inhibitors. 对HIV-1进入抑制剂的耐药性。

Current drug targets. Infectious disorders Pub Date : 2003-12-01 DOI: 10.2174/1568005033481015

W C Olson, P J Maddon

引用次数: 21

Fitness variations and their impact on the evolution of antiretroviral drug resistance. 适应度变异及其对抗逆转录病毒耐药性进化的影响。

Current drug targets. Infectious disorders Pub Date : 2003-12-01 DOI: 10.2174/1568005033481033

Luis Menéndez-Arias, Miguel A Martínez, Miguel E Quiñones-Mateu, Javier Martinez-Picado

{"title":"Fitness variations and their impact on the evolution of antiretroviral drug resistance.","authors":"Luis Menéndez-Arias, Miguel A Martínez, Miguel E Quiñones-Mateu, Javier Martinez-Picado","doi":"10.2174/1568005033481033","DOIUrl":"https://doi.org/10.2174/1568005033481033","url":null,"abstract":"The human immunodeficiency virus (HIV) exhibits extensive heterogeneity due to its rapid turnover, high mutation rate, and high frequency of recombination. Its remarkable genetic diversity plays a key role in virus adaptation, including development of drug resistance. The increasing complexity of antiretroviral regimens has favored selection of HIV variants harboring multiple drug resistance mutations. Evolution of drug resistance is characterized by severe fitness losses, which can be partially overcome by compensatory mutations or other adaptive changes that restore virus replication capacity. Recent reports have addressed the impact of drug-resistance mutations on viral fitness. Methods include in vitro estimates based on the determination of viral replication kinetics, viral infectivity in single-cycle assays and growth competition experiments; as well as estimates of the relative fitness of viral populations in vivo calculated from standard population genetics theory. This review focuses on the effects in viral fitness of mutations arising during treatment with reverse transcriptase and protease inhibitors, and the molecular mechanisms (including compensatory mutations) that improve the viral fitness of drug-resistant variants.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 4","pages":"355-71"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24188942","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: 46

Variety of interpretation systems for human immunodeficiency virus type 1 genotyping: confirmatory information or additional confusion? 人类免疫缺陷病毒1型基因分型的各种解释系统:确认信息还是额外的混淆?

Current drug targets. Infectious disorders Pub Date : 2003-12-01 DOI: 10.2174/1568005033481006

M Stürmer, H W Doerr, W Preiser

{"title":"Variety of interpretation systems for human immunodeficiency virus type 1 genotyping: confirmatory information or additional confusion?","authors":"M Stürmer, H W Doerr, W Preiser","doi":"10.2174/1568005033481006","DOIUrl":"https://doi.org/10.2174/1568005033481006","url":null,"abstract":"The emergence of drug resistance remains a major problem during antiretroviral treatment of patients infected with human immunodeficiency virus type 1 (HIV-1). As phenotypic drug resistance is laborious and expensive to determine, and because numerous specific mutations are known to be correlated with different resistance patterns, genotyping of the reverse transcriptase and protease genes of HIV is fast becoming an integral part of HIV management in industrialized countries. A number of software-based interpretation systems have been developed for the interpretation of the resulting complex nucleotide sequences. These programs either employ rule-based algorithms or are based on a genotype-phenotype database. This paper reviews recent publications that compare different such systems, trying to identify the degree of discordance between different systems and the reasons underlying such discrepant interpretations. The highest discordance rate was observed for nucleoside reverse transcriptase inhibitors (NRTIs) followed by protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). For the NRTIs, it is the role of nucleoside analogue associated mutations, for the PIs and for the NNRTIs, that of secondary mutations that causes most discrepancies. As the complexity of the mutation pattern is likely to increase further with new drugs becoming available, rule-based genotype interpretation algorithms need to be updated frequently. Whilst not recommending one particular system, the authors believe that the correlation of genotypic with clinical data is probably the best way to develop an optimal algorithm.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 4","pages":"373-82"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24188943","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: 28

Preface [Hot topic: HIV Drug Resistance and Approaches to New Therapies (Guest Editor: Chris Petropoulos)] 前言[热门话题:HIV耐药性和新疗法的方法(特邀编辑:Chris Petropoulos)]

Current drug targets. Infectious disorders Pub Date : 2003-11-30 DOI: 10.2174/1568005310303040III

R. Goldman

引用次数: 0