Discovery of a Direct Ras Inhibitor by Screening a
Combinatorial Library of Cell-Permeable Bicyclic Peptides
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Abstract
Cyclic
peptides have great potential as therapeutic agents and research tools.
However, their applications against intracellular targets have been
limited, because cyclic peptides are generally impermeable to the
cell membrane. It was previously shown that fusion of cyclic peptides
with a cyclic cell-penetrating peptide resulted in cell-permeable
bicyclic peptides that are proteolytically stable and biologically
active in cellular assays. In this work, we tested the generality
of the bicyclic approach by synthesizing a combinatorial library of
5.7 × 10<sup>6</sup> bicyclic peptides featuring a degenerate
sequence in the first ring and an invariant cell-penetrating peptide
in the second ring. Screening of the library against oncoprotein K-Ras
G12V followed by hit optimization produced a moderately potent and
cell-permeable K-Ras inhibitor, which physically blocks the Ras-effector
interactions in vitro, inhibits the signaling events downstream of
Ras in cancer cells, and induces apoptosis of the cancer cells. Our
approach should be generally applicable to developing cell-permeable
bicyclic peptide inhibitors against other intracellular proteins