TY - JOUR
T1 - Novel superactive leptin antagonists and their potential therapeutic applications
AU - Gertler, Arieh
AU - Elinav, Eran
N1 - Israel Science Foundation [521/07] This work was supported by the Israel Science Foundation, grant no. 521/07 to AG and EE. The authors thank the members of their teams for their valuable contribution to this work: Dr. Leonora Niv-Spector, Dr. Michal Shpilman, Ms. Gili Solomon from the Hebrew University of Jerusalem, and Ms. Meirav Katz and Dr. Chen Varol from Tel-Aviv Sourasky Medical Center.
PY - 2014
Y1 - 2014
N2 - Random mutagenesis of mouse leptin antagonist (L39A/D40A/F41) followed by selection of high-affinity mutants by yeastsurface display indicated that replacing residue D23 with a non-negatively charged amino acid (most specifically with Leu) leads to dramatically enhanced affinity of leptin toward LEPR leading to development of superactive mouse, human, ovine and rat leptin antagonists (D23L/L39A/D40A/F41A). Superactive leptin antagonist mutants of mouse, human, rat or ovine leptins were developed in our laboratory, expressed in E. coli, refolded and purified to homogeneity as monomeric proteins. Pegylation of leptin antagonists resulted in potent and effective long-acting reagents suitable for in vivo studies or therapies. In the present review we explain the mechanism of leptin inhibition and summarize the possible use of leptin antagonists as possible leptin blockers in various human pathologies such as antiinflammatory and anti-autoimmune diseases, uremic cachexia, and cancer. We also suggest the use of leptin antagonists as research reagents for creation of a novel, fast and reversible model of T2DM in mice.
AB - Random mutagenesis of mouse leptin antagonist (L39A/D40A/F41) followed by selection of high-affinity mutants by yeastsurface display indicated that replacing residue D23 with a non-negatively charged amino acid (most specifically with Leu) leads to dramatically enhanced affinity of leptin toward LEPR leading to development of superactive mouse, human, ovine and rat leptin antagonists (D23L/L39A/D40A/F41A). Superactive leptin antagonist mutants of mouse, human, rat or ovine leptins were developed in our laboratory, expressed in E. coli, refolded and purified to homogeneity as monomeric proteins. Pegylation of leptin antagonists resulted in potent and effective long-acting reagents suitable for in vivo studies or therapies. In the present review we explain the mechanism of leptin inhibition and summarize the possible use of leptin antagonists as possible leptin blockers in various human pathologies such as antiinflammatory and anti-autoimmune diseases, uremic cachexia, and cancer. We also suggest the use of leptin antagonists as research reagents for creation of a novel, fast and reversible model of T2DM in mice.
UR - http://www.scopus.com/inward/record.url?scp=84894105717&partnerID=8YFLogxK
U2 - https://doi.org/10.2174/13816128113199990014
DO - https://doi.org/10.2174/13816128113199990014
M3 - مقالة مرجعية
SN - 1381-6128
VL - 20
SP - 659
EP - 665
JO - Current Pharmaceutical Design
JF - Current Pharmaceutical Design
IS - 4
ER -