Details
| Original language | English |
|---|---|
| Pages (from-to) | 2408-2421 |
| Number of pages | 14 |
| Journal | Molecular therapy |
| Volume | 31 |
| Issue number | 8 |
| Early online date | 4 Jul 2023 |
| Publication status | Published - 2 Aug 2023 |
Abstract
Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMP-activated protein kinase (AMPK) complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an adeno-associated virus (AAV)-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK-stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis, and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof of concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development toward a novel, first-in-class approach against cancer cachexia.
Keywords
- adipose tissue, AMPK, cachexia, cancer, metabolic dysfunction, peptide-drug
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Genetics
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmacology
- Pharmacology, Toxicology and Pharmaceutics(all)
- Drug Discovery
Sustainable Development Goals
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In: Molecular therapy, Vol. 31, No. 8, 02.08.2023, p. 2408-2421.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Development of a peptide drug restoring AMPK and adipose tissue functionality in cancer cachexia
AU - Ji, Honglei
AU - Englmaier, Felix
AU - Morigny, Pauline
AU - Giroud, Maude
AU - Gräsle, Pamina
AU - Brings, Sebastian
AU - Szendrödi, Julia
AU - Berriel Diaz, Mauricio
AU - Plettenburg, Oliver
AU - Herzig, Stephan
AU - Rohm, Maria
N1 - Funding Information: We thank Luke Harrison for the creation of the graphical abstract and help with text editing, Raúl Terrón Expósito and Daniela Hass for technical assistance, and Anja Zeigerer for help with microscopy. We thank Ez-Zoubir Amri for the hMADSCs. The graphical abstract was created with BioRender.com. Molecular graphics and analyses performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. M.G. was supported by an Alexander von Humboldt Foundation postdoctoral fellowship. M.R. is funded by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (# 949017) and Helmholtz Association - Initiative and Networking Fund. Conceptualization, O.P. S.H. and M.R.; data curation and formal analysis, H.J. F.E. P.M. M.G. S.B. P.G. J.S. M.B.D. and M.R.; investigation and methodology, H.J. F.E. and M.R.; visualization, H.J. F.E. S.B. and M.R.; writing – original draft, H.J. and M.R.; writing – review & editing, H.J. F.E. S.B. J.S. O.P. S.H. and M.R. This work was in part supported by research grants by Novo Nordisk to O.P. S.H. and M.R. Funding Information: This work was in part supported by research grants by Novo Nordisk to O.P., S.H., and M.R. Funding Information: We thank Luke Harrison for the creation of the graphical abstract and help with text editing, Raúl Terrón Expósito and Daniela Hass for technical assistance, and Anja Zeigerer for help with microscopy. We thank Ez-Zoubir Amri for the hMADSCs. The graphical abstract was created with BioRender.com . Molecular graphics and analyses performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology , National Institute of Allergy and Infectious Diseases . M.G. was supported by an Alexander von Humboldt Foundation postdoctoral fellowship. M.R. is funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program ( # 949017 ) and Helmholtz Association - Initiative and Networking Fund. Funding Information: Molecular graphics and analyses performed with UCSF ChimeraX, 44 developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases.
PY - 2023/8/2
Y1 - 2023/8/2
N2 - Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMP-activated protein kinase (AMPK) complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an adeno-associated virus (AAV)-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK-stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis, and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof of concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development toward a novel, first-in-class approach against cancer cachexia.
AB - Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMP-activated protein kinase (AMPK) complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an adeno-associated virus (AAV)-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK-stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis, and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof of concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development toward a novel, first-in-class approach against cancer cachexia.
KW - adipose tissue
KW - AMPK
KW - cachexia
KW - cancer
KW - metabolic dysfunction
KW - peptide-drug
UR - http://www.scopus.com/inward/record.url?scp=85165375991&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2023.06.020
DO - 10.1016/j.ymthe.2023.06.020
M3 - Article
C2 - 37408309
AN - SCOPUS:85165375991
VL - 31
SP - 2408
EP - 2421
JO - Molecular therapy
JF - Molecular therapy
SN - 1525-0016
IS - 8
ER -