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Ji, H. ; Englmaier, F. ; Morigny, P. ; Giroud, M. ; Gräsle, P. ; Brings, S.* ; Szendrödi, J.* ; Berriel Diaz, M. ; Plettenburg, O. ; Herzig, S. ; Rohm, M.

Development of a peptide drug restoring AMPK and adipose tissue functionality in cancer cachexia.

Mol. Ther. 31, 2408-2421 (2023)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Adipose Tissue ; Ampk ; Cachexia ; Cancer ; Metabolic Dysfunction ; Peptide-drug; Activated Protein-kinase; Cell-penetrating Peptides; Body-composition; Lipolysis; Adipocytes; Phosphorylation; Transcription; Homeostasis; Metabolism; Mechanism
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 1525-0016
e-ISSN 1525-0024
Zeitschrift Molecular Therapy
Quellenangaben Band: 31, Heft: 8, Seiten: 2408-2421 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Institute of Medicinal Chemistry (IMC)
POF Topic(s) 90000 - German Center for Diabetes Research
30203 - Molecular Targets and Therapies
Forschungsfeld(er) Helmholtz Diabetes Center
Enabling and Novel Technologies
PSP-Element(e) G-501900-257
G-501900-251
G-506300-001
G-501900-253
Förderungen NIGMS NIH HHS
DOI 10.1016/j.ymthe.2023.06.020
WOS ID 001053039300001
Scopus ID 85165375991
PubMed ID 37408309
Erfassungsdatum 2023-10-18
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