Peptide-based leptin receptor antagonists for cancer treatment and appetite regulation

Biopolymers. 2011;96(2):117-25. doi: 10.1002/bip.21377.


Leptin, a multifunctional hormone, controls various processes in both the central nervous system and in peripheral tissues. Because of the presence of multiple leptin/receptor (ObR) interaction sites and diverse leptin activities, the literature lacks truly monofunctional leptin protein derivatives or fragments. To date, selective ObR antagonists have not been reported. We developed short, pharmacologically advantageous peptide analogs of ObR-binding site III of leptin that acted as selective ObR inhibitors without any partial agonistic activity. These reduced leptin-dependent growth and signaling in cancer cell lines at picomolar and low nanomolar concentrations. In immunocompromised mice the peptides suppressed the growth of rapidly proliferating orthotopic human breast cancer xenografts by 50% when administered either intraperitoneally (i.p.) or subcutaneously (s.c.) for 38 days at a 0.1 mg/kg/day dose. The peptides were distributed to the brain, and when added to growing C57BL/6 normal mice i.p., s.c., or orally, the lead antagonist accelerated normal weight increase without producing any toxic effects. Weight gain increases could not be observed after 10-12 days of treatment indicating that the mice became resistant to the central nervous system activity of leptin antagonists. However, in normal growing rats the intranasal administration at 0.1 mg/kg/day for 20 days resulted in a 2% net total body weight gain without signs of resistance induction. In addition to the potential of these peptides in drug development against primary and metastatic tumors and cachexia, our data confirm that resistance to leptin resides at the blood-brain barrier.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Appetite / drug effects*
  • Appetite Stimulants / chemistry
  • Appetite Stimulants / pharmacology*
  • Binding Sites
  • Cell Line
  • Female
  • Humans
  • Leptin / chemistry
  • Leptin / pharmacology*
  • Male
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / physiopathology
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Rats
  • Rats, Inbred F344
  • Receptors, Leptin / agonists


  • Antineoplastic Agents
  • Appetite Stimulants
  • Leptin
  • Oligopeptides
  • Peptides
  • Receptors, Leptin
  • leptin receptor, human
  • leptin receptor, mouse
  • threonyl-glutamyl-norvalyl-alanyl-leucyl-leucyl-seryl-arginyl-aminocaproamide