1 research outputs found
Cell-Permeable Stapled Peptides Based on HIVā1 Integrase Inhibitors Derived from HIVā1 Gene Products
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 Ī±-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 Ī±-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 Ī±-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 (<b>2</b>) but with lower cytotoxicity. Fluorescent imaging experiments revealed
that these stapled peptides are significantly cell permeable, and
CD analysis showed they form Ī±-helical structures, whereas the
unstapled congeners form Ī²-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