2 research outputs found
Discovery of a Direct Ras Inhibitor by Screening a Combinatorial Library of Cell-Permeable Bicyclic Peptides
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 Ă— 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
Screening Bicyclic Peptide Libraries for Protein–Protein Interaction Inhibitors: Discovery of a Tumor Necrosis Factor‑α Antagonist
Protein–protein
interactions represent a new class of exciting but challenging drug
targets, because their large, flat binding sites lack well-defined
pockets for small molecules to bind. We report here a methodology
for chemical synthesis and screening of large combinatorial libraries
of bicyclic peptides displayed on rigid small-molecule scaffolds.
With planar trimesic acid as the scaffold, the resulting bicyclic
peptides are effective for binding to protein surfaces such as the
interfaces of protein–protein interactions. Screening of a
bicyclic peptide library against tumor necrosis factor-α (TNFα)
identified a potent antagonist that inhibits the TNFα–TNFα
receptor interaction and protects cells from TNFα-induced cell
death. Bicyclic peptides of this type may provide a general solution
for inhibition of protein–protein interactions