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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.

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Presented in this paper is a general purpose computer model for predicting transdermal permeation of solutes in vivo. The “bricks and mortar” model is employed to represent the stratum corneum (SC), the main barrier to transdermal permeation. Transdermal permeation and absorption is modeled as a dynamic process of mass transfer in the heterogeneous stratum corneum including both the tortuous lipid pathway and the transcellular corneocytes pathway. The partition and diffusion properties of solutes in SC lipid matrix and corneocytes are calculated from the fundamental physical chemical properties of octanol−water partition coefficient, molecular size, and diffusion coefficients in water and lipid, using equations established elsewhere. To test the model, the in vivo tape striping data of 4-cyanophenol is simulated. Using the calculated partition and diffusion properties of 4-cyanophenol in SC lipids and corneocytes, the predicted dynamic profiles of 4-cyanophenol in the SC agreed very well with the experimental data. Results show that for a moderately hydrophobic solute like 4-cyanophenol, the transcellular pathway is also an important route of percutaneous absorption with about 2/3 of the absorbed 4-cyanophenol partitioned into the corneocytes.