CD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.

Here, we describe the generation of a novel type of HIV entry inhibitor using the recently developed Designed Ankyrin Repeat Protein (DARPin) technology. DARPin proteins specific for human CD4 were selected from a DARPin DNA library using ribosome display. Selected pool members interacted specifical...

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Autores principales:	Andreas Schweizer, Peter Rusert, Livia Berlinger, Claudia R Ruprecht, Axel Mann, Stéphanie Corthésy, Stuart G Turville, Meropi Aravantinou, Marek Fischer, Melissa Robbiani, Patrick Amstutz, Alexandra Trkola
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/63f2e46f9bed439bb295b004f6d2249c
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spelling	oai:doaj.org-article:63f2e46f9bed439bb295b004f6d2249c2021-11-25T05:46:29ZCD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.1553-73661553-737410.1371/journal.ppat.1000109https://doaj.org/article/63f2e46f9bed439bb295b004f6d2249c2008-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18654624/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Here, we describe the generation of a novel type of HIV entry inhibitor using the recently developed Designed Ankyrin Repeat Protein (DARPin) technology. DARPin proteins specific for human CD4 were selected from a DARPin DNA library using ribosome display. Selected pool members interacted specifically with CD4 and competed with gp120 for binding to CD4. DARPin proteins derived in the initial selection series inhibited HIV in a dose-dependent manner, but showed a relatively high variability in their capacity to block replication of patient isolates on primary CD4 T cells. In consequence, a second series of CD4-specific DARPins with improved affinity for CD4 was generated. These 2nd series DARPins potently inhibit infection of genetically divergent (subtype B and C) HIV isolates in the low nanomolar range, independent of coreceptor usage. Importantly, the actions of the CD4 binding DARPins were highly specific: no effect on cell viability or activation, CD4 memory cell function, or interference with CD4-independent virus entry was observed. These novel CD4 targeting molecules described here combine the unique characteristics of DARPins-high physical stability, specificity and low production costs-with the capacity to potently block HIV entry, rendering them promising candidates for microbicide development.Andreas SchweizerPeter RusertLivia BerlingerClaudia R RuprechtAxel MannStéphanie CorthésyStuart G TurvilleMeropi AravantinouMarek FischerMelissa RobbianiPatrick AmstutzAlexandra TrkolaPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 4, Iss 7, p e1000109 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Andreas Schweizer Peter Rusert Livia Berlinger Claudia R Ruprecht Axel Mann Stéphanie Corthésy Stuart G Turville Meropi Aravantinou Marek Fischer Melissa Robbiani Patrick Amstutz Alexandra Trkola CD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.
description	Here, we describe the generation of a novel type of HIV entry inhibitor using the recently developed Designed Ankyrin Repeat Protein (DARPin) technology. DARPin proteins specific for human CD4 were selected from a DARPin DNA library using ribosome display. Selected pool members interacted specifically with CD4 and competed with gp120 for binding to CD4. DARPin proteins derived in the initial selection series inhibited HIV in a dose-dependent manner, but showed a relatively high variability in their capacity to block replication of patient isolates on primary CD4 T cells. In consequence, a second series of CD4-specific DARPins with improved affinity for CD4 was generated. These 2nd series DARPins potently inhibit infection of genetically divergent (subtype B and C) HIV isolates in the low nanomolar range, independent of coreceptor usage. Importantly, the actions of the CD4 binding DARPins were highly specific: no effect on cell viability or activation, CD4 memory cell function, or interference with CD4-independent virus entry was observed. These novel CD4 targeting molecules described here combine the unique characteristics of DARPins-high physical stability, specificity and low production costs-with the capacity to potently block HIV entry, rendering them promising candidates for microbicide development.
format	article
author	Andreas Schweizer Peter Rusert Livia Berlinger Claudia R Ruprecht Axel Mann Stéphanie Corthésy Stuart G Turville Meropi Aravantinou Marek Fischer Melissa Robbiani Patrick Amstutz Alexandra Trkola
author_facet	Andreas Schweizer Peter Rusert Livia Berlinger Claudia R Ruprecht Axel Mann Stéphanie Corthésy Stuart G Turville Meropi Aravantinou Marek Fischer Melissa Robbiani Patrick Amstutz Alexandra Trkola
author_sort	Andreas Schweizer
title	CD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.
title_short	CD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.
title_full	CD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.
title_fullStr	CD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.
title_full_unstemmed	CD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.
title_sort	cd4-specific designed ankyrin repeat proteins are novel potent hiv entry inhibitors with unique characteristics.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/63f2e46f9bed439bb295b004f6d2249c
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CD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.

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