PuSH - Publication Server of Helmholtz Zentrum München: Long-acting human PASylated leptin reaches the murine central nervous system and offers potential for optimized replacement therapy.

Information

Clues to quality of journals

Open Access Policy of Helmholtz Association 2016

CC Licencences

Publication Metrics

Navigation

Home

Deutsch

Research

Advanced Search

Browse by ...

... HMGU-Authors/Consortia

... Organizational Structure

... Journal

... Publication Type

... Research Data

... Arbeitsgruppen

... Publication Year

Publication overview

Statistics

Statistics (last 5 years)

OA Publications

Publish

Submit Publication

Import publication from...

...EVA

Report missing publication

Highlights

Support & Contact

Contact persons

Help

Data protection

Helmholtz Open Science

JANE Journal Estimator

SHERPA/RoMEO

DOAJ

Export:

Text

Endnote (RIS) BIB

BibTeX

Morath, V.* ; Maurer, S.* ; Feuchtinger, A. ; Walser, R.* ; Schlapschy, M.* ; Bolze, F.* ; Metzler, T.* ; Bruder, J.* ; Steiger, K.* ; Walch, A.K. ; Klingenspor, M.* ; Skerra, A.*

Long-acting human PASylated leptin reaches the murine central nervous system and offers potential for optimized replacement therapy.

Mol. Pharm. 22, 3017-3032 (2025)

Publ. Version/Full Text

DOI

PMC

	Open Access Hybrid

Abstract
Metrics
Extra information

Despite the multifaceted role of leptin for energy homeostasis and its broad therapeutic potential, the FDA/EMA-approved metreleptin constitutes the only leptin drug to date. To translate the promising results from previous studies on murine PASylated leptin with improved solubility and extended plasma half-life using PASylation technology─a biological alternative to PEGylation─we have developed a second-generation human leptin drug candidate and tested it rigorously in vitro and in vivo. To this end, the exposed hydrophobic Trp residue at position 100 in human leptin was replaced by Gln, which, together with the genetic fusion with a 600-residue PAS polypeptide, yielded a protein with high solubility, folding stability and receptor-stimulatory activity. In a pharmacokinetic (PK) study with wild-type mice, this modified human leptin showed an extended plasma half-life of 18.8 ± 3.6 h after subcutaneous (s.c.) injection. Furthermore, leptin-deficient mice were dosed s.c. with the modified human leptin carrying two different PAS fusion tags, PAS#1 or P/A#1, each comprising 600 residues. After only four doses, the disease phenotype, including morbid adiposity, hyperphagia, and hepatic steatosis, was completely reversed by both PASylated leptin versions, but not by the non-PASylated leptin if administered at the same dose. To assess its tissue distribution, P/A(200)-huLeptin^W100Q was doubly labeled with two fluorescent dyes, which were specifically attached to the leptin and the PAS moiety, respectively. Analysis of relevant mouse organs by light sheet fluorescence microscopy after clearance revealed colocalized signals in the kidney and liver, thus indicating general stability of the PAS-leptin fusion protein in vivo. However, discrete signals were observed in the hypothalamic region, only with leptin detectable in the choroid plexus, which implies cleavage of the PAS tag during transcytosis across the physiological barriers. This study should pave the way toward a second-generation leptin drug enabling prolonged dosing intervals.

Impact Factor

Scopus SNIP

Altmetric

4.500

0.000