TY - JOUR
T1 - Engineered Peptide Coacervates Enable Efficient Intracellular Delivery of the MYC Inhibitor omoMYC
AU - Cerrato, Carmine P.
AU - Krkoška, Martin
AU - Sun, Yue
AU - Liaño-Pons, Judit
AU - Neo, Qi Ying
AU - Vosselman, Thibault
AU - Alzrigat, Mohammad
AU - Vojtěšek, Borek
AU - Lane, David P.
AU - Arsenian Henriksson, Marie
AU - Miserez, Ali
AU - Landreh, Michael
N1 - Publisher Copyright:
© 2025 The Authors. Published by American Chemical Society.
PY - 2025
Y1 - 2025
N2 - Intracellular delivery is a bottleneck in the development of therapeutic peptides and proteins. Here, we demonstrate the efficient delivery of omoMYC, the first MYC inhibitor in clinical trials, using HBpep-SP, an engineered peptide forming liquid-liquid phase-separated coacervates. HBpep-SP coacervates facilitate efficient cellular uptake and intracellular delivery of the omoMYC peptide at concentrations lower than those required for spontaneous uptake. Strikingly, omoMYC coacervates result in reduced proliferation and apoptosis induction in the low c-MYC expressing cell lines HEK293 and SH-SY5Y cells, but not in HeLa and SK-N-BE(2) cells with high c-MYC/MYCN expression, respectively, suggesting that endogenous MYC/N levels may impact the effects of omoMYC. Importantly, our approach bypasses the need for cell penetration-enhancing chemical modifications, offering a novel strategy for the investigation of peptide drug mechanisms in therapeutic development.
AB - Intracellular delivery is a bottleneck in the development of therapeutic peptides and proteins. Here, we demonstrate the efficient delivery of omoMYC, the first MYC inhibitor in clinical trials, using HBpep-SP, an engineered peptide forming liquid-liquid phase-separated coacervates. HBpep-SP coacervates facilitate efficient cellular uptake and intracellular delivery of the omoMYC peptide at concentrations lower than those required for spontaneous uptake. Strikingly, omoMYC coacervates result in reduced proliferation and apoptosis induction in the low c-MYC expressing cell lines HEK293 and SH-SY5Y cells, but not in HeLa and SK-N-BE(2) cells with high c-MYC/MYCN expression, respectively, suggesting that endogenous MYC/N levels may impact the effects of omoMYC. Importantly, our approach bypasses the need for cell penetration-enhancing chemical modifications, offering a novel strategy for the investigation of peptide drug mechanisms in therapeutic development.
KW - drug delivery
KW - liquid−liquid phase separation
KW - protein engineering
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U2 - 10.1021/acs.molpharmaceut.5c00468
DO - 10.1021/acs.molpharmaceut.5c00468
M3 - Article
AN - SCOPUS:105004042966
SN - 1543-8384
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
ER -