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

verfasst von

Honglei Ji, Felix Englmaier, Pauline Morigny, Maude Giroud, Pamina Gräsle, Sebastian Brings, Julia Szendrödi, Mauricio Berriel Diaz, Oliver Plettenburg, Stephan Herzig, Maria Rohm

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.

Organisationseinheit(en)

Institut für Organische Chemie

Externe Organisation(en)

Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Ruprecht-Karls-Universität Heidelberg
Deutsches Zentrum für Diabetesforschung e.V. (DZD)
Institute for Lung Health (ILH)
Technische Universität München (TUM)

Typ

Artikel

Journal

Molecular therapy

Band

31

Seiten

2408-2421

Anzahl der Seiten

14

ISSN

1525-0016

Publikationsdatum

02.08.2023

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Molekularmedizin, Molekularbiologie, Genetik, Pharmakologie, Wirkstoffforschung

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1016/j.ymthe.2023.06.020 (Zugang: Offen)