The Development of a Leptin Receptor Antagonist through Peptide and Peptoid Synthesis and Analysis via Surface Plasmon Resonance

Abstract

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by its lack of estrogen receptors, progesterone receptors, and human epidermal growth factor 2 receptors. Because these receptors are not found within TNBC, a targeted therapeutic against TNBC has yet to be developed. We believe that there is sufficient evidence to suggest that targeting the leptin receptor (ObR) may elicit therapeutic affects against TNBC. Known antagonists to ObR include the peptide molecules LDFI and Allo-aca. A general problem facing peptide therapeutics is a characteristic 10-12 minute half-life in the human body due to non-specific proteases, not allowing enough time for the intended mechanism of action to have its desired effect. To address this issue, we created peptoid peptidomimetic versions of LDFI and Allo-aca in the forms of N-LDFI and N-Allo-aca-biotin. Peptoids are not subject to non-specific protease degradation and therefore have no known general half-life within the human body while also retaining very similar structures to their peptide counterparts. We used localized surface plasmon resonance, which detects binding affinities between molecules, to determine if N-LDFI and N-Allo-aca had similar binding affinities to ObR in comparison to LDFI and Allo-aca. Through this testing we were able to determine that LDFI has a binding affinity to ObR of Kd = 2.32×10-8 M and that N-LDFI does bind to ObR, though we are not confident of its binding affinity. We were unable to determine the binding affinities of Allo-aca and N-All-aca to ObR due to what we believe were either flaws in or methodology or unknown malfunctions with the instrument we used to perform localized surface plasmon resonance.