title: Design of cell-permeable stapled peptides as HIV-1 integrase inhibitors.
abstract: HIV-1 integrase (IN) catalyzes the integration of viral DNA into the host genome, involving several interactions with the viral and cellular proteins. We have previously identified peptide IN inhibitors derived from the α-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 IN inhibitors but also prototypical biochemical probes or "nanoneedles" for the elucidation of HIV-1 IN dimerization and host cofactor interactions within their native cellular environment.
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Ya-Qiu
authors.initials: YQ
authors.lastname: Long
authors.forename: Shao-Xu
authors.initials: SX
authors.lastname: Huang
authors.forename: Zahrah
authors.initials: Z
authors.lastname: Zawahir
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Xu
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Li
authors.forename: Tino W
authors.initials: TW
authors.lastname: Sanchez
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhi
authors.forename: Stephanie
authors.initials: S
authors.lastname: De Houwer
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D055162:Biocatalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D045325:HCT116 Cells; D019427:HIV Integrase / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D018613:Microscopy, Confocal; D008956:Models, Chemical; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology / Q000821:virology; D011485:Protein Binding / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; C504649:PSIP1 protein, human; D010455:Peptides; D014157:Transcription Factors; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1