Novel Superactive Leptin Antagonists and their Potential Therapeutic Applications

Title:Novel Superactive Leptin Antagonists and their Potential Therapeutic Applications

Volume: 20 Issue: 4

Author(s): Arieh Gertler and Eran Elinav

Affiliation:

Keywords: Leptin, antagonist, inflammatory disease, anti-autoimmune diseases, cancer, uremic cachexia, T2DM model.

Abstract: 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.

Cite this article as:

Gertler Arieh and Elinav Eran, Novel Superactive Leptin Antagonists and their Potential Therapeutic Applications, Current Pharmaceutical Design 2014; 20 (4) . https://dx.doi.org/10.2174/13816128113199990014