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CD4 mimetic miniproteins: potent anti-HIV compounds with promising activity as microbicides

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dc.contributor.author Van Herrewege, Y. en_US
dc.contributor.author Morellato, L. en_US
dc.contributor.author Descours, A. en_US
dc.contributor.author Aerts, L. en_US
dc.contributor.author Michiels, J. en_US
dc.contributor.author Heyndrickx, L. en_US
dc.contributor.author Martin, L. en_US
dc.contributor.author Vanham, G. en_US
dc.date.accessioned 2008-05-20T13:14:36Z
dc.date.available 2008-05-20T13:14:36Z
dc.date.issued 2008
dc.identifier.issn 0305-7453
dc.identifier.doi http://dx.doi.org/10.1093/jac/dkn042
dc.identifier.other ITG-M1A en_US
dc.identifier.other ITG-M4B en_US
dc.identifier.other ITG-M5B en_US
dc.identifier.other ITG-M6A en_US
dc.identifier.other ITG-MLA en_US
dc.identifier.other MICRO en_US
dc.identifier.other U-VIROL en_US
dc.identifier.other JIF en_US
dc.identifier.other DOI en_US
dc.identifier.other UPD3 en_US
dc.identifier.other ABSTRACT en_US
dc.identifier.uri http://hdl.handle.net/10390/2259
dc.description.abstract OBJECTIVES: The antiviral activity of CD4 miniproteins was evaluated as potential HIV microbicides, using relevant in vitro models. METHODS: Compounds were tested in a single-cycle HIV-1 pseudovirus assay and against replication competent HIV-1 in co-cultures of monocyte-derived dendritic cells (MO-DC) and CD4+ T cells. Cytotoxic activity was evaluated in an MTT assay. RESULTS: Monomeric miniproteins (M47 and M48) showed 50% effective concentration (EC(50)) values of 79-105 nM against a subtype B, CCR5 co-receptor-using Ba-L pseudovirus. Higher activity was found for the dimeric miniproteins M48D30, M48D50 and M48D100 (EC(50) between 15 and 30 nM), in contrast to the tetrameric miniproteins M48T30, M48T50 and M48T100 (EC(50) between 107 and 377 nM). The hetero-bivalent miniprotein M48-Hep and miniproteins that targeted the Phe-43 cavity on gp120 (M48-U1, M48-U2 and M48-U3) were highly active, with EC(50) values as low as 2 nM for M48-U1. All miniproteins showed high activity against CCR5 or CXCR4 co-receptor-using subtype B and CRF-01_A/E pseudoviruses. Many early M48-based compounds were much less active against subtype C pseudoviruses, whereas M48-U compounds that targeted the Phe-43 cavity were very active against all pseudoviruses, including subtype C. In MO-DC/CD4+ T cell co-cultures with replication-competent HIV-1 Ba-L, EC(50) values ranged between 13 and 1719 nM depending on the miniprotein, with M48-U1, M48-U2 and M48-U3 again being the most potent. Importantly, the latter compounds completely prevented viral replication by treating the cultures from 2 h before until 24 h after infection, at non-toxic concentrations of 66-6564 nM. CONCLUSIONS: These novel CD4 miniproteins might constitute a promising class of HIV microbicides.
dc.subject Viral diseases en_US
dc.subject HIV en_US
dc.subject AIDS en_US
dc.subject Microbicides en_US
dc.subject CD4 miniproteins en_US
dc.subject Evaluation en_US
dc.title CD4 mimetic miniproteins: potent anti-HIV compounds with promising activity as microbicides en_US
dc.type Article en_US
dc.citation.issue 4 en_US
dc.citation.jtitle Journal of Antimicrobial Chemotherapy en_US
dc.citation.volume 61 en_US
dc.citation.pages 818-826
dc.identifier.pmid http://www.ncbi.nlm.nih.gov/pubmed/18270220
dc.citation.jabbreviation J Antimicrob Chemother en_US


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