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