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Cell-permeable stapled peptides based on HIV-1 integrase inhibitors derived from HIV-1 gene products.

Authors :
Nomura W
Aikawa H
Ohashi N
Urano E
Métifiot M
Fujino M
Maddali K
Ozaki T
Nozue A
Narumi T
Hashimoto C
Tanaka T
Pommier Y
Yamamoto N
Komano JA
Murakami T
Tamamura H
Source :
ACS chemical biology [ACS Chem Biol] 2013 Oct 18; Vol. 8 (10), pp. 2235-44. Date of Electronic Publication: 2013 Aug 15.
Publication Year :
2013

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.

Details

Language :
English
ISSN :
1554-8937
Volume :
8
Issue :
10
Database :
MEDLINE
Journal :
ACS chemical biology
Publication Type :
Academic Journal
Accession number :
23898787
Full Text :
https://doi.org/10.1021/cb400495h