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Blockade of chemokine (C-X-C motif) receptor 4 for the inhibition of hepatocellular carcinoma metastasisKok, Tsz-wai., 郭梓瑋. January 2008 (has links)
published_or_final_version / Surgery / Doctoral / Doctor of Philosophy
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Mechanism study of novel CCR5 antagonists and their potential as anti-HIV-1 microbicidesKang, Yuanxi., 康元曦. January 2012 (has links)
R5-tropic HIV-1 is predominantly transmitted during unprotected sexual contacts, rendering CCR5 antagonist as an attractive agent not only for antiretroviral therapy but also for prevention. Here, we report two 1,3,3,4-tetrasubstituted pyrrolidine embodied compounds, TD-0232 and TD-0680, as novel small molecule CCR5 antagonists and investigate their specificities, potencies and underlying mechanisms. We found that both TD-0232 and TD-0680 inhibited a diverse group of R5-tropic HIV-1 and SIV strains in both single-cycle infectivity assays and live viral PBMC assays. When compared to other CCR5 antagonists, such as TAK-779 and the only FDA-approved Maraviroc, TD-0680 displayed the highest potency with EC50 values at the subnanomolar levels (range 0.09nM-2.29nM). TD-0232 and TD-0680, but not Tenofovir, a nucleoside reverse transcriptase inhibitor, completely blocked envelope-mediated cell-cell fusion and subsequent viral transmission. Critically, TD-0680 was potent at inhibiting the replication of a TAK-779/Maraviroc-resistant HIV-1 variant in PBMCs at a subnanomolar concentration.
Interestingly, despite binding to a similar transmembrane pocket of CCR5, TD-0232 and TD-0680 functioned differently as revealed by site-directed mutagenesis and drug combination assays. Based on the sequence homology, we constructed a CCR5 molecule model using the crystallized CXCR4 as a template. By docking of CCR5 antagonists with CCR5, we identified a unique binding mode of TD-0680, which has not been described previously. TD-0680, with an exo-configuration, extended its interaction with the ECL-2 region of CCR5 in a protruding manner, thereby interrupting the interaction between the virus and its co-receptor more effectively. In an antibody recognition assay, we confirmed that TD-0680 had an enhanced inhibitory activity against the anti-ECL2 monoclonal antibodies binding.
Furthermore, we investigated the antiviral activities of TD-0232 and TD-0680 that were formulated into a thermo-reversible acidic microbicide gel. Both drugs were stable in the acidic gels and could be released rapidly for long lasting and potent antiviral activities. Although human semen could enhance the infection of HIV-1, it did not seem to affect the potencies of the TD-0232 and TD-0680 gels.
In summary, our findings suggest that TD-0232 and TD-0680 can be further developed not only as anti-HIV-1 agents for therapeutic purposes but also as potent microbicides for the prevention of sexual transmission of R5-tropic HIV-1. / published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy
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Mammalian and viral chemokines provide insight into the mechanism of chemokine receptor activationDavis, Christopher Nathan, January 2004 (has links)
Thesis (Ph. D.)--University of Florida, 2004. / Title from title page of source document. Document formatted into pages; contains 145 pages. Includes vita. Includes bibliographical references.
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Chemokines and their role in dopaminergic developmentEdman, Linda C., January 2009 (has links)
Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009.
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CXCR4 and FOXO3a expression in breast cancerCheuk, Tin-hoi., 卓殿凱. January 2011 (has links)
published_or_final_version / Pathology / Master / Master of Medical Sciences
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The role of chemokine and chemokine receptor genes in genetic susceptibility to HIV infection in South AfricaPetersen, Desiree C. 03 1900 (has links)
Thesis (MSc)--Stellenbosch University, 2002. / ENGLISH ABSTRACT:
Please see fulltext for abstract / AFRIKAANSE OPSOMMING:
Sien asb volteks vir opsomming
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Rôle de FANCA dans la régulation de la neddylation de protéines membranaires. / Role of the FANCA protein in neddylation of membrane associated proteins.Renaudin, Xavier 17 September 2014 (has links)
Le but de cette thèse était d’identifier de nouveaux substrats au complexe FANC Core,déficient dans l’Anémie de Fanconi, une pathologie génétique rare. Cette maladie estcaractérisée par un phénotype hétérogène associant une pancytopénie à des malformationscongénitales et une prédisposition accrues aux leucémies myéloïdes aigues.L’anémie de Fanconi est causée par la mutation biallélique dans un des seize gènesFANC. Les protéines produites par ces gènes participent à une même voie moléculaireimpliquée dans la signalisation des dommages de l’ADN. Huit de ces protéines forment lecomplexe FANC Core, une E3 ubiquitine ligase, dont les seuls substrats à ce jour sontFANCD2 et FANCI.Dans le but d’identifier de nouveaux substrats du complexe FANC Core, j’ai réalisé uneanalyse protéomique après immunoprécipitation des peptides modifiés par l’ubiquitine ou parles ubiquitin-like NEDD8 et ISG15. Cette expérience a été faite dans des cellules déficientespour la voie FANC, mutées sur les gène FANCA ou FANCC et comparée à des cellulescorrigées par l’expression de ces gènes.Cette analyse révèle que FANCD2 et FANCI sont les seules cibles du complexe FANCCore en réponse à des dommages de l’ADN.Néanmoins, je montre l’existence d’autres protéines qui sont modifiées d’une manièreFANCA dépendante. Ces protéines sont pour la grande majorité des protéines membranairesou associées aux membranes cytoplasmiques. Parmi celles-ci, j’ai pu déterminer que lerécepteur aux chimiokines, CXCR5, était modifié d’une manière FANCA dépendante parl’ubiquitin-like NEDD8. Cette modification impacte sur la localisation de la protéine à lamembrane et à des conséquences sur la migration des cellules.J’ai aussi montré que FANCA participe d’une manière similaire à la régulation de lalocalisation membranaire d’autres protéines comme APLP2.Ainsi, il est proposé par ce travail un rôle de la protéine FANCA en dehors du complexeFANC Core et en dehors de la réparation des dommages à l’ADN. Comment la protéineFANCA participe à la régulation du trafic des protéines membranaires reste un point nonrésolu à ce jour. / The aim of this thesis was to find new substrates of the E3-ubiquitin ligase activity of theFANC Core complex, mutated in the rare genetic disorder Fanconi Anemia. This disease ischaracterized by bone marrow failure, developmental abnormalities and predisposition tocancer. Eight of the 16 known FANC proteins participate in the FANCcore nuclear complex,which has E3 ubiquitin-ligase activity and monoubiquitinates FANCD2 and FANCI inresponse to replication stress.In this thesis, I used mass spectrometry to compare cellular extracts from FANC Corecomplex deficient FA-A and FA-C cells to their ectopically corrected counterparts after agenotoxic stress.FANCD2 and FANCI appear to be the only true direct targets of the FANCcore complex.However, I also identified other proteins that undergo post-translational modifications throughFANCA- or FANCC-specific direct or indirect mechanisms that are independent of theFANCcore complex. The majority of these potential FANCA or FANCC target proteinslocalize to the cell membrane.Finally, I demonstrated that (a) the chemokine receptor CXCR5 is a neddylated protein; (b)FANCA, surprisingly, appears to modulate CXCR5 neddylation through a currently unknownmechanism; (c) CXCR5 neddylation is involved in the targeting of this receptor to the cellmembrane; and (d) CXCR5 neddylation stimulates cell migration/motility.I also confirmed that the role of FANCA in neddylation is not restrict to CXCR5 but also to,at least, one other protein, APLP2.My work has uncovered a new signaling pathway that is potentially involved in the rarehuman syndrome Fanconi Anemia and in cell motility and has highlighted a potential newfunction for the FANCA protein independant of the FANC Core complex and of a genotoxicstress.
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Thymic stromal cells : population dynamics and their role in thymopoiesisGray, Daniel Herbert Donald January 2003 (has links)
Abstract not available
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