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

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