Current drug targets. Infectious disorders最新文献_第9页

Targeted inhibition of angiogenic factors in AIDS-related disorders. 艾滋病相关疾病中血管生成因子的靶向抑制。

Current drug targets. Infectious disorders Pub Date : 2003-06-01 DOI: 10.2174/1568005033481222

Yoshiyasu Aoki, Giovanna Tosato

{"title":"Targeted inhibition of angiogenic factors in AIDS-related disorders.","authors":"Yoshiyasu Aoki, Giovanna Tosato","doi":"10.2174/1568005033481222","DOIUrl":"https://doi.org/10.2174/1568005033481222","url":null,"abstract":"Immunosuppression associated with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) markedly increases the risk for development of several cancers. Despite its dramatic decrease in frequency after the introduction of highly active antiretroviral therapy (HAART), Kaposi's sarcoma (KS) remains the most common neoplastic manifestation of AIDS. KS is a multicentric angioproliferative tumor, characterized microscopically by spindle cells. KS cells produce and respond to angiogenic factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF-A). In addition to cellular growth factors, the trans-activator HIV protein Tat plays a major role in the pathogenesis of AIDS-related KS by augmenting the angiogenic activities of bFGF and VEGF-A, and activating the VEGF receptor-2. Viral products from the recently described Kaposi's sarcoma-associated herpesvirus (KSHV) also exhibit potent angiogenic activities. KSHV is consistently associated with KS and two lymphoproliferative disorders, primary effusion lymphoma (PEL) and the plasma cell variant of multicentric Castleman's disease (MCD). Several viral genes may contribute to the phenotype of PEL and MCD: among them, a viral homologue of interleukin-6 (vIL-6) has attracted much attention due to its potential to stimulate B cell growth and accelerate angiogenesis via VEGF-A induction. In this review, we summarize current knowledge and hypothesis regarding the cellular and viral angiogenic factors involved in the pathogeneses of AIDS-related malignancies, and discuss novel therapeutic strategies based on targeting pro-angiogenic factors.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 2","pages":"115-28"},"PeriodicalIF":0.0,"publicationDate":"2003-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22404856","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: 26

CD8+ T-cell-mediated non-cytolytic suppression of human immuno-deficiency viruses. CD8+ t细胞介导的人免疫缺陷病毒的非细胞溶解性抑制。

Current drug targets. Infectious disorders Pub Date : 2003-06-01 DOI: 10.2174/1568005033481196

C Vella, R S Daniels

{"title":"CD8+ T-cell-mediated non-cytolytic suppression of human immuno-deficiency viruses.","authors":"C Vella, R S Daniels","doi":"10.2174/1568005033481196","DOIUrl":"https://doi.org/10.2174/1568005033481196","url":null,"abstract":"Major histocompatibility (MHC)-restricted cytotoxic T-lymphocytes (CTL) kill human immunodeficiency virus (HIV)-infected cells. In addition, activated CD8(+) T-lymphocytes from HIV-infected individuals suppress virus replication in vitro by producing antiviral factor (CAF). The effector mechanism(s) of CAF involves modulation of HIV gene transcription, is non-cytolytic and mediated in part by soluble antiviral factors. Initially, CAF activity was shown to be more vigorous in activated CD8(+) cells and cell free supernatants (SNs) from asymptomatic individuals compared to those with AIDS, suggesting a protective role in vivo. CAF-mediated suppression is also evident in animal models of immunodeficiency virus infection. Several soluble molecules that contribute to non-cytolytic virus suppression have been characterised, including alpha- and beta-chemokines and interleukin-16 (IL-16), but these are distinct from CAF. Two agents possessing certain CAF-like characteristics, modified antithrombin 111 (AT111) and the human alpha-defensins, have been described but their antiviral mechanisms are not fully understood. CAF-secretion may not be virus-specific as similar activity is found in activated CD8(+) cells/SNs from humans and chimpanzees seronegative for HIV-1. Recent data indicates that the secretion of CAF is MHC-restricted and both cytolytic and non-cytolytic mechanisms are mediated by CTL. If the latter is correct, a single appropriate stimulus could be used to enhance both effector mechanisms in vivo. This paper reviews research aimed at characterising HIV-suppressive factors and raises other questions that must be considered for the development of prophylactic and therapeutic strategies leading to the safe and effective control of HIV.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 2","pages":"97-113"},"PeriodicalIF":0.0,"publicationDate":"2003-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22404855","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: 13

Particle-based vaccines for HIV-1 infection. 针对HIV-1感染的颗粒疫苗。

Current drug targets. Infectious disorders Pub Date : 2003-06-01 DOI: 10.2174/1568005033481213

Kelly R Young, Ted M Ross

{"title":"Particle-based vaccines for HIV-1 infection.","authors":"Kelly R Young, Ted M Ross","doi":"10.2174/1568005033481213","DOIUrl":"https://doi.org/10.2174/1568005033481213","url":null,"abstract":"The use of live-attenuated viruses as vaccines has been successful for the control of viral infections. However, the development of an effective vaccine against the human immunodeficiency virus (HIV) has proven to be a challenge. HIV infects cells of the immune system and results in a severe immunodeficiency. In addition, the ability of the virus to adapt to immune pressure and the ability to reside in an integrated form in host cells present hurdles for vaccinologists to overcome. A particle-based vaccine strategy has promise for eliciting high titer, long-lived, immune responses to a diverse number of viral epitopes from different HIV antigens. Live-attenuated viruses are effective at generating both cellular and humoral immunity, however, a live-attenuated vaccine for HIV is problematic. The possibility of a live-attenuated vaccine to revert to a pathogenic form or recombine with a wild-type or defective virus in an infected individual is a drawback to this approach. Therefore, these vaccines are currently only being tested in non-human primate models. Live-attenuated vaccines are effective in stimulating immunity, however challenged animals rarely clear viral infection and the degree of attenuation directly correlates with the protection of animals from disease. Another particle-based vaccine approach for HIV involves the use of virus-like particles (VLPs). VLPs mimic the viral particle without causing an immunodeficiency disease. HIV-like particles (HIV-LP) are defined as self-assembling, non-replicating, nonpathogenic, genomeless particles that are similar in size and conformation to intact virions. A variety of VLPs for both HIV and SIV are currently in pre-clinical and clinical trials. This review focuses on the current knowledge regarding the immunogenicity and safety of particle-based vaccine strategies for HIV-1.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 2","pages":"151-69"},"PeriodicalIF":0.0,"publicationDate":"2003-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22404859","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: 33

Chitin synthesis as target for antifungal drugs. 几丁质合成作为抗真菌药物的靶点。

Current drug targets. Infectious disorders Pub Date : 2003-03-01 DOI: 10.2174/1568005033342064

J Ruiz-Herrera, G San-Blas

{"title":"Chitin synthesis as target for antifungal drugs.","authors":"J Ruiz-Herrera, G San-Blas","doi":"10.2174/1568005033342064","DOIUrl":"https://doi.org/10.2174/1568005033342064","url":null,"abstract":"Human mycoses have become a threat to health world-wide. Unfortunately there are only a limited number of antimycotic drugs in use. Promising targets for drugs specific against fungi are those affecting chitin synthesis. Chitin is absent in vertebrates, and is essential for fungal wall integrity. A thorough knowledge of the mechanism of chitin synthesis is required to design specific inhibitors. We review here our current understanding of the process, and the most promising drugs that inhibit it. Chitin is made by chitin synthases requiring specific microvesicles, the chitosomes, for intracellular transport. Fungi contain several chitin synthases, some of which may be essential at a certain stage. This phenomenon is important to take into account for drug design. The most widely studied chitin synthase inhibitors are polyoxins and nikkomycins that probably bind to the catalytic site of chitin synthases. These are not equally susceptible to the drugs. In Saccharomyces cerevisiae the order of sensitivity is: Chs3p>Chs1p>Chs2p. Main problems for their succesful use in vivo are: low permeability, and different susceptibility of fungal species, and variable responses in animal models. Chemical modifications have been proposed to make more potent derivatives. Other synthetic or natural compounds are also promising as possible inhibitors, but their properties are less well known. Rational drug design has proceeded only on the basis of existing inhibitors, because the structure of the active site of chitin synthase is unknown. Undoubtedly, determination of this, and the biosynthetic mechanism will reveal unexpected drug targets in the future.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 1","pages":"77-91"},"PeriodicalIF":0.0,"publicationDate":"2003-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005033342064","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22231863","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: 91

Strategy of computer-aided drug design. 计算机辅助药物设计策略。

Current drug targets. Infectious disorders Pub Date : 2003-03-01 DOI: 10.2174/1568005033342145

A V Veselovsky, A S Ivanov

引用次数: 91

Antivirals at the mirror: the lack of stereospecificity of some viral and human enzymes offers novel opportunities in antiviral drug development. 镜像抗病毒药物:一些病毒和人类酶缺乏立体特异性为抗病毒药物的开发提供了新的机会。

Current drug targets. Infectious disorders Pub Date : 2003-03-01 DOI: 10.2174/1568005033342163

Federico Focher, Silvio Spadari, Giovanni Maga

{"title":"Antivirals at the mirror: the lack of stereospecificity of some viral and human enzymes offers novel opportunities in antiviral drug development.","authors":"Federico Focher, Silvio Spadari, Giovanni Maga","doi":"10.2174/1568005033342163","DOIUrl":"https://doi.org/10.2174/1568005033342163","url":null,"abstract":"The enantioselectivity of enzymes, namely the property of enzymes to recognise and metabolise only one of the two enantiomers of chiral molecules, is related to the chiral structure of the enzymes, reflecting the three-dimensional folding of the polypeptide backbone and the orientation of the amino acid side chains in the folded molecule. Because of the chirality of the amino acids (L), the chemistry of life should be highly sensitive to different enantiomers of chiral substrates. However, in a world consisting only of D-nucleosides and L-amino acids, an enzyme which lacks enantio-selectivity does not reduce its fitness, since there is no chance of molecular misunderstanding when no other choice is available. Thus, although enantioselectivity is theoretically essential for life we do not expect to be always present among the biochemical properties of enzymes. If this is the case for key enzymes involved in virus infection or cancer, how to exploit such lack of enantioselectivity for a novel approach to antiviral or anticancer chemotherapy? The present review will discuss the possible lack of enantioselectivity of enzymes and its relevance for the developing of novel drugs with the inverted optical configuration.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 1","pages":"41-53"},"PeriodicalIF":0.0,"publicationDate":"2003-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005033342163","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22230667","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: 19

New approaches for anti-infective drug discovery: antibiotics, vaccines and beyond. 发现抗感染药物的新途径:抗生素、疫苗等。

Current drug targets. Infectious disorders Pub Date : 2003-03-01 DOI: 10.2174/1568005033342082

Q Cheng, S Wang, A A Salyers

引用次数: 9

Beta-lactamases: a survey of protein diversity. β -内酰胺酶:蛋白质多样性的调查。

Current drug targets. Infectious disorders Pub Date : 2003-03-01 DOI: 10.2174/1568005033342181

Marion S Helfand, Robert A Bonomo

{"title":"Beta-lactamases: a survey of protein diversity.","authors":"Marion S Helfand, Robert A Bonomo","doi":"10.2174/1568005033342181","DOIUrl":"https://doi.org/10.2174/1568005033342181","url":null,"abstract":"Bacterial resistance to beta-lactam antibiotics and beta-lactamase inhibitors is an ever increasing problem that threatens the clinical utility of drugs that form the cornerstone of the antibiotic armamentarium. Especially among Gram-negative pathogens, elaboration of structurally and mechanistically novel beta-lactamase enzymes is the most important means by which resistance occurs. An appreciation of the tremendous diversity of these drug-modifying enzymes will assist in understanding why so few generally effective inhibitory agents exist for these unique drug targets. This review will give a general background on the reaction mechanisms and classification schemes of the more than 340 beta-lactamase enzymes described to date. A discussion will follow highlighting the emerging Class A SHV and TEM-derived extended-spectrum (ESBLs), and inhibitor-resistant enzymes, non-TEM, non-SHV Class A ESBLs, and carbapenemases, Class B metallo-beta-lactamases and some of their novel inhibitors, plasmid and chromosomally encoded Class C enzymes, and finally, the OXA-type oxacillinases, ESBLs, and carbapenemases of Class D. The clinical importance of multiple resistance mechanisms in conjunction with the production of beta-lactamase enzymes is emphasized.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 1","pages":"9-23"},"PeriodicalIF":0.0,"publicationDate":"2003-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005033342181","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22230664","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: 81

Therapy of chronic hepatitis C: a critical review. 慢性丙型肝炎的治疗:一个重要的回顾。

Current drug targets. Infectious disorders Pub Date : 2003-03-01 DOI: 10.2174/1568005033342127

G Saracco, A Olivero, A Ciancio, S Carenzi, M Rizzetto

{"title":"Therapy of chronic hepatitis C: a critical review.","authors":"G Saracco, A Olivero, A Ciancio, S Carenzi, M Rizzetto","doi":"10.2174/1568005033342127","DOIUrl":"https://doi.org/10.2174/1568005033342127","url":null,"abstract":"Combination therapy (Interferon plus ribavirin) is the current therapeutic gold standard for naive Hepatitis C Virus (HCV)-positive patients and with the recent advent of pegylated (PEG) IFN the rate of the sustained virological response (HCV-RNA clearance 6 months after the end of treatment) is about 54%-56% with a therapeutical gain mainly among patients with unfavourable HCV genotype (1a, 1b); in this subset of patients, a 42%-46% sustained response rate is achieved compared with 33%-36% found among genotype 1 patients treated with the standard therapy. Patients who respond to IFN monotherapy but relapse during the follow-up should be re-treated with combination therapy given for at least 6 months at the minimum dose of 3 MU thrice weekly plus ribavirin 1000 mg/daily. Recent data suggest that prolonging the time of treatment (12 months) may induce a significantly higher rate of sustained response among patients with genotype 1. The efficacy of the combination of IFN and ribavirin in retreating patients with chronic hepatitis C not responding to IFN monotherapy is controversial as it ranges between 0% and 40%. Recent data show an overall rate of sustained response of 23% when an aggressive approach is adopted but increasing the dosage and the time of treatment induces a significant therapeutic benefit only in patients with genotype 1. In conclusion, a therapeutic progress for chronic hepatitis C has been achieved during the last 10 years (56% vs 20% of sustained response rate obtained with IFN monotherapy) but several unresolved issues are yet to be addressed.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 1","pages":"25-32"},"PeriodicalIF":0.0,"publicationDate":"2003-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22230665","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

Mode of action of plant defensins suggests therapeutic potential. 植物防御素的作用方式提示治疗潜力。

Current drug targets. Infectious disorders Pub Date : 2003-03-01 DOI: 10.2174/1568005033342000

Bart P H J Thomma, Bruno P A Cammue, Karin Thevissen

引用次数: 77