Engineered Peptide Coacervates Enable Efficient Intracellular Delivery of the MYC Inhibitor omoMYC

Carmine P. Cerrato; Martin Krkoška; Yue Sun; Judit Liaño-Pons; Qi Ying Neo; Thibault Vosselman; Mohammad Alzrigat; Borek Vojtěšek; David P. Lane; Marie Arsenian Henriksson; Ali Miserez; Michael Landreh

doi:10.1021/acs.molpharmaceut.5c00468

Engineered Peptide Coacervates Enable Efficient Intracellular Delivery of the MYC Inhibitor omoMYC

Carmine P. Cerrato, Martin Krkoška, Yue Sun, Judit Liaño-Pons, Qi Ying Neo, Thibault Vosselman, Mohammad Alzrigat, Borek Vojtěšek, David P. Lane, Marie Arsenian Henriksson^*, Ali Miserez^*, Michael Landreh^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Journal	Molecular Pharmaceutics
DOIs	https://doi.org/10.1021/acs.molpharmaceut.5c00468
Publication status	Accepted/In press - 2025
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2025 The Authors. Published by American Chemical Society.

ASJC Scopus Subject Areas

Molecular Medicine
Pharmaceutical Science
Drug Discovery

Keywords

drug delivery
liquid−liquid phase separation
protein engineering

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10.1021/acs.molpharmaceut.5c00468

Cite this

Cerrato, C. P., Krkoška, M., Sun, Y., Liaño-Pons, J., Neo, Q. Y., Vosselman, T., Alzrigat, M., Vojtěšek, B., Lane, D. P., Arsenian Henriksson, M., Miserez, A., & Landreh, M. (Accepted/In press). Engineered Peptide Coacervates Enable Efficient Intracellular Delivery of the MYC Inhibitor omoMYC. Molecular Pharmaceutics. https://doi.org/10.1021/acs.molpharmaceut.5c00468

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abstract = "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.",

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author = "Cerrato, {Carmine P.} and Martin Krko{\v s}ka and Yue Sun and Judit Lia{\~n}o-Pons and Neo, {Qi Ying} and Thibault Vosselman and Mohammad Alzrigat and Borek Vojt{\v e}{\v s}ek and Lane, {David P.} and {Arsenian Henriksson}, Marie and Ali Miserez and Michael Landreh",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors. Published by American Chemical Society.",

year = "2025",

doi = "10.1021/acs.molpharmaceut.5c00468",

language = "English",

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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

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.

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Engineered Peptide Coacervates Enable Efficient Intracellular Delivery of the MYC Inhibitor omoMYC

Abstract

Bibliographical note

ASJC Scopus Subject Areas

Keywords

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