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Abstract
Peptide modulators targeting protein-protein interactions (PPIs) exhibit greater potential
than small-molecule drugs in several important aspects including facile modification
and relative large contact surface area. Stabilized peptides constructed by variable
chemistry methods exhibit improved peptide stability and cell permeability compared
to that of the linears. Herein, we designed a stabilized peptide-based proteolysis-targeting
chimera (PROTAC) targeting estrogen receptor α (ERα) by tethering an N-terminal aspartic
acid cross-linked stabilized peptide ERα modulator (TD-PERM) with a pentapeptide that
binds the Von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. The resulting heterobifunctional
peptide (TD-PROTAC) selectively recruits ERα to the VHL E3 ligase complex, leading
to the degradation of ERα in a proteasome-dependent manner. Compared with the control
peptides, TD-PROTAC shows significantly enhanced activities in reducing the transcription
of the ERα-downstream genes and inhibiting the proliferation of ERα-positive breast
cancer cells. In addition, in vivo experiments indicate that TD-PROTAC leads to tumor
regression in the MCF-7 mouse xenograft model. This work is a successful attempt to
construct PROTACs based on cell-permeable stabilized peptides, which significantly
broadens the chemical space of PROTACs and stabilized peptides.