Charge-Based Optimization of Neurotensin for Neurotensin-Receptor-1 Targeting Utilizing a One-Bead One-Compound Peptide Library Approach

Author

Trey Neeley, University of Nebraska Medical CenterFollow

Graduation Date

Fall 12-20-2019

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Pharmaceutical Sciences

First Advisor

Jered C. Garrison, Ph.D.

Second Advisor

Nicholas T. Woods, Ph.D.

Third Advisor

Erika I. Boesen, Ph.D.

Fourth Advisor

Corey R. Hopkins, Ph.D.

Abstract

Neurotensin-receptor-1 (NTSR1) is regularly overexpressed in various cancers and contributes to the proliferation, survival, migration, invasion, and angiogenesis of tumors. NTSR1-targeting vectors have demonstrated promise in both diagnostic and therapeutic aspects. Unfortunately, the relatively poor in vivo metabolic stability and high renal uptake and retention of NTSR1-targeted compounds have hampered the translation to the clinic. In this research, we utilized a one-bead one-compound (OBOC) peptide library approach to make targeted modifications at the naturally charged residues of an NTS (4-13) sequence to discover an NTS derivative with comparable affinity to NTSR1, acceptable in vivo stability, and tolerable renal retention. Subsequent in vitro screening and analysis by LC-MS/MS and PEAKS® Studio software determined the modifications of interest for further investigation with the most favorable observed binding affinity toward NTSR1 were Gln at Glu⁴, Lys(Me₂) at Lys⁶, and Arg(NO₂) at Arg⁹.

Recommended Citation

Neeley, Trey, "Charge-Based Optimization of Neurotensin for Neurotensin-Receptor-1 Targeting Utilizing a One-Bead One-Compound Peptide Library Approach" (2019). Theses & Dissertations. 394.
https://digitalcommons.unmc.edu/etd/394