Development of a peptide drug restoring AMPK and adipose tissue functionality in cancer cachexia.
AMPK
adipose tissue
cachexia
cancer
metabolic dysfunction
peptide-drug
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
02 08 2023
02 08 2023
Historique:
received:
28
03
2023
revised:
01
06
2023
accepted:
30
06
2023
pmc-release:
02
08
2024
medline:
7
8
2023
pubmed:
6
7
2023
entrez:
6
7
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37408309
pii: S1525-0016(23)00380-5
doi: 10.1016/j.ymthe.2023.06.020
pmc: PMC10422018
pii:
doi:
Substances chimiques
AMP-Activated Protein Kinases
EC 2.7.11.31
Peptides
0
Pharmaceutical Preparations
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2408-2421Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM129325
Pays : United States
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests This work was in part supported by research grants by Novo Nordisk to O.P., S.H., and M.R.
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