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Title: Design of cell-permeable stapled-peptides as HIV-1 integrase inhibitors
Authors: Long, Ya-Qiu
Huang, Shao-Xu
Zawahir, Zahrah
Xu, Zhong-Liang
Li, Hui-Yuan
Sanchez, Tino W
Zhi, Ying
De Houwer, St├ęphanie
Christ, Frauke
Debyser, Zeger
Neamati, Nouri # ×
Issue Date: Jun-2013
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:56 issue:13 pages:5601-5612
Abstract: HIV-1 integrase (IN) catalyzes the integration of viral DNA into the host genome, involving several interactions with host proteins. We have previously identified peptide IN inhibitors derived from the alpha-helical regions along the dimeric interface of HIV-1 IN. Herein, we show that appropriate hydrocarbon-stapling of these peptides to stabilize their helical structure remarkably improves the cell permeability, thus allowing inhibition of the HIV-1 replication in cell culture. Furthermore, the stabilized peptides inhibit the interaction of IN with the cellular cofactor LEDGF/p75. Cellular uptake of the stapled peptide was confirmed in four different cell lines using a fluorescein-labeled analogue. Given their enhanced potency and cell permeability, these stapled peptides can serve as not only lead compounds of novel HIV-1 IN inhibitors but also prototypical biochemical probes or 'nanoneedles' for the elucidation of HIV-1 IN dimerization and host co-factor interactions within their native cellular environment.
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Virology and Gene Therapy
× corresponding author
# (joint) last author

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