title: Novel superactive leptin antagonists and their potential therapeutic applications.
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.
authors.forename: Arieh
authors.initials: A
authors.lastname: Gertler
authors.affiliation: The Hebrew University, The Robert H. Smith Faculty of Agriculture, Food and Environment, Rehovot 76100, Israel. gertler@agri.huji.ac.il.
authors.forename: Eran
authors.initials: E
authors.lastname: Elinav
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015551:Autoimmunity / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D015195:Drug Design; D015507:Drugs, Investigational / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D020738:Leptin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000235:genetics; D008024:Ligands; D050505:Mutant Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D020738:Leptin; D008024:Ligands; D050505:Mutant Proteins; D054411:Receptors, Leptin; D011994:Recombinant Proteins