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      In Vitro Activity of Geldanamycin Derivatives against Schistosoma japonicum and Brugia malayi

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          Abstract

          Geldanamycin (GA) is a benzoquinone-containing ansamycin that inhibits heat shock protein 90. GA derivatives are being evaluated as anti-neoplastic agents, but their utility against parasites whose heat shock proteins (Hsps) have homology with human Hsp90 is unknown. The activities of four synthetic GA derivatives were tested in vitro using adult Brugia malayi and Schistosoma japonicum. Two of the derivatives, 17- N-allyl-17-demethoxygeldanamycin (17-AAG) and 17- N-(2-dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG), are currently in human clinical trials as anticancer drugs. Using concentrations considered safe peak plasma concentrations for these two derivatives, all four derivatives were active against both parasites. The less toxic derivative 17-AAG was as effective as GA in killing S. japonicum, and both DMAG and 5′-bromogeldanoxazinone were more active than 17-AAG against B. malayi. This work supports continued evaluation of ansamycin derivatives as broad spectrum antiparasitic agents.

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          Comparative genomics and evolution of the HSP90 family of genes across all kingdoms of organisms

          Bin Chen, Daibin Zhong, Antónia Monteiro (2006)
          Background HSP90 proteins are essential molecular chaperones involved in signal transduction, cell cycle control, stress management, and folding, degradation, and transport of proteins. HSP90 proteins have been found in a variety of organisms suggesting that they are ancient and conserved. In this study we investigate the nuclear genomes of 32 species across all kingdoms of organisms, and all sequences available in GenBank, and address the diversity, evolution, gene structure, conservation and nomenclature of the HSP90 family of genes across all organisms. Results Twelve new genes and a new type HSP90C2 were identified. The chromosomal location, exon splicing, and prediction of whether they are functional copies were documented, as well as the amino acid length and molecular mass of their polypeptides. The conserved regions across all protein sequences, and signature sequences in each subfamily were determined, and a standardized nomenclature system for this gene family is presented. The proeukaryote HSP90 homologue, HTPG, exists in most Bacteria species but not in Archaea, and it evolved into three lineages (Groups A, B and C) via two gene duplication events. None of the organellar-localized HSP90s were derived from endosymbionts of early eukaryotes. Mitochondrial TRAP and endoplasmic reticulum HSP90B separately originated from the ancestors of HTPG Group A in Firmicutes-like organisms very early in the formation of the eukaryotic cell. TRAP is monophyletic and present in all Animalia and some Protista species, while HSP90B is paraphyletic and present in all eukaryotes with the exception of some Fungi species, which appear to have lost it. Both HSP90C (chloroplast HSP90C1 and location-undetermined SP90C2) and cytosolic HSP90A are monophyletic, and originated from HSP90B by independent gene duplications. HSP90C exists only in Plantae, and was duplicated into HSP90C1 and HSP90C2 isoforms in higher plants. HSP90A occurs across all eukaryotes, and duplicated into HSP90AA and HSP90AB in vertebrates. Diplomonadida was identified as the most basal organism in the eukaryote lineage. Conclusion The present study presents the first comparative genomic study and evolutionary analysis of the HSP90 family of genes across all kingdoms of organisms. HSP90 family members underwent multiple duplications and also subsequent losses during their evolution. This study established an overall framework of information for the family of genes, which may facilitate and stimulate the study of this gene family across all organisms.
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            Heat shock proteins as emerging therapeutic targets.

            Csaba Sőti, Enikő Nagy, Zoltan Giricz … (2005)
            Chaperones (stress proteins) are essential proteins to help the formation and maintenance of the proper conformation of other proteins and to promote cell survival after a large variety of environmental stresses. Therefore, normal chaperone function is a key factor for endogenous stress adaptation of several tissues. However, altered chaperone function has been associated with the development of several diseases; therefore, modulators of chaperone activities became a new and emerging field of drug development. Inhibition of the 90 kDa heat shock protein (Hsp)90 recently emerged as a very promising tool to combat various forms of cancer. On the other hand, the induction of the 70 kDa Hsp70 has been proved to be an efficient help in the recovery from a large number of diseases, such as, for example, ischemic heart disease, diabetes and neurodegeneration. Development of membrane-interacting drugs to modify specific membrane domains, thereby modulating heat shock response, may be of considerable therapeutic benefit as well. In this review, we give an overview of the therapeutic approaches and list some of the key questions of drug development in this novel and promising therapeutic approach.
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              Heat shock protein 90 function is essential for Plasmodium falciparum growth in human erythrocytes.

              S Pavithra, Varsha Singh, Utpal Tatu … (2003)
              Hsp90 is important for normal growth and development in eukaryotes. Together with Hsp70 and other accessory proteins, Hsp90 not only helps newly synthesized proteins to fold but also regulates activities of transcription factors and protein kinases. Although the gene coding for heat shock protein 90 from Plasmodium falciparum (PfHsp90) has been characterized previously, there is very little known regarding its function in the parasite. We have analyzed PfHsp90 complexes and addressed its role in parasite life cycle using Geldanamycin (GA), a drug known to interfere with Hsp90 function. Sedimentation analysis and size exclusion chromatography showed PfHsp90 to be in 11 s(20,(w)) complexes of approximately 300 kDa in size. Similar to the hetero-oligomeric complexes of Hsp90 in mammals, PfHsp70 was found to be present in PfHsp90 complexes. Homology modeling revealed a putative GA-binding pocket at the amino terminus of PfHsp90. The addition of GA inhibited parasite growth with LD(50) of 0.2 microm. GA inhibited parasite growth by arresting transition from Ring to trophozoite. Transition from trophozoite to schizonts and reinvasion of new erythrocytes were less significantly affected. While inducing the synthesis of PfHsp70 and PfHsp90, GA did not significantly alter the pattern of newly synthesized proteins. Pre-exposure to heat shock attenuated GA-mediated growth inhibition, suggesting the involvement of heat shock proteins. Specificity of GA action on PfHsp90 was evident from selective inhibition of PfHsp90 phosphorylation in GA-treated cultures. In addition to suggesting an essential role for PfHsp90 during parasite growth, our results highlight PfHsp90 as a potential drug target to control malaria.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Parasitol Res
                Journal ID (publisher-id): JPR
                Title: Journal of Parasitology Research
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 2090-0023
                ISSN (Electronic): 2090-0031
                Publication date (Print): 2010
                Publication date (Electronic): 29 December 2010
                Volume: 2010
                Electronic Location Identifier: 716498
                Affiliations
                1The Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
                2Department of Biochemistry, University of the Philippines, Manila, Philippines
                3Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Avenue Appia 20, 1211 Geneva 27, Switzerland
                4Biotechnology and Bioengineering Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
                Author notes
                *David Wenkert: wenkert@ 123456msu.edu

                Academic Editor: Nirbhay Kumar

                Article
                DOI: 10.1155/2010/716498
                PMC ID: 3021863
                PubMed ID: 21253549
                SO-VID: 5a8ebb83-9af9-4bd8-a92a-9ab1b232c41d
                Copyright © Copyright © 2010 David Wenkert et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 15 June 2010
                Date revision received : 22 October 2010
                Date accepted : 23 November 2010
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Parasitology
                Data availability:
                ScienceOpen disciplines: Parasitology

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