title: Cell-permeable stapled peptides based on HIV-1 integrase inhibitors derived from HIV-1 gene products.
abstract: HIV-1 integrase (IN) is an enzyme which is indispensable for the stable infection of host cells because it catalyzes the insertion of viral DNA into the genome and thus is an attractive target for the development of anti-HIV agents. Earlier, we found Vpr-derived peptides with inhibitory activity against HIV-1 IN. These Vpr-derived peptides are originally located in an α-helical region of the parent Vpr protein. Addition of an octa-arginyl group to the inhibitory peptides caused significant inhibition against HIV replication associated with an increase in cell permeability but also relatively high cytotoxicity. In the current study, stapled peptides, a new class of stabilized α-helical peptidomimetics were adopted to enhance the cell permeability of the above lead peptides. A series of stapled peptides, which have a hydrocarbon link formed by a ruthenium-catalyzed ring-closing metathesis reaction between successive turns of α-helix, were designed, synthesized, and evaluated for biological activity. In cell-based assays some of the stapled peptides showed potent anti-HIV activity comparable with that of the original octa-arginine-containing peptide (2) but with lower cytotoxicity. Fluorescent imaging experiments revealed that these stapled peptides are significantly cell permeable, and CD analysis showed they form α-helical structures, whereas the unstapled congeners form β-sheet structures. The application of this stapling strategy to Vpr-derived IN inhibitory peptides led to a remarkable increase in their potency in cells and a significant reduction of their cytotoxicity.
authors.affiliation: Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering , Tokyo Medical and Dental University , 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nomura
authors.forename: Haruo
authors.initials: H
authors.lastname: Aikawa
authors.forename: Nami
authors.initials: N
authors.lastname: Ohashi
authors.forename: Emiko
authors.initials: E
authors.lastname: Urano
authors.forename: Mathieu
authors.initials: M
authors.lastname: Métifiot
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujino
authors.forename: Kasthuraiah
authors.initials: K
authors.lastname: Maddali
authors.forename: Taro
authors.initials: T
authors.lastname: Ozaki
authors.forename: Ami
authors.initials: A
authors.lastname: Nozue
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Narumi
authors.forename: Chie
authors.initials: C
authors.lastname: Hashimoto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Jun A
authors.initials: JA
authors.lastname: Komano
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Murakami
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002942:Circular Dichroism; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D057786:Peptidomimetics; D011485:Protein Binding
chemical_list: D019428:HIV Integrase Inhibitors; D010455:Peptides; D057786:Peptidomimetics; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
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