Identification, Characterization, and Optimization of Integrin αvβ6-Targeting Peptides from a One-Bead One-Compound (OBOC) Library: Towards the development of positron emission tomography (PET) imaging agents

Yng C. Tang, Ryan A. Davis, Tanushree Ganguly, Julie Sutcliffe

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

The current translation of peptides identified through the one-bead one-compound (OBOC) technology into positron emission tomography (PET) imaging agents is a slow process, with a major delay between ligand identification and subsequent lead optimization. This work aims to streamline the development process of 18F-peptide based PET imaging agents to target the integrin αvβ6. By directly identify αvβ6–targeting peptides from a 9-mer 4-fluorobenzoyl peptide library using the on-bead two-color (OBTC) cell-screening assay, a total of 185 peptide beads were identified and 5 beads sequenced for further evaluation. The lead peptide 1 (VGDLTYLKK(FB), IC50 = 0.45 ± 0.06 µM, 25% stable in serum at 1 h) was further modified at the N-, C-, and bi-termini. C-terminal PEGylation increased the metabolic stability (>95% stable), but decreased binding affinity (IC50 = 3.7 ± 1 µM) was noted. C-terminal extension (1i, VGDLTYLKK(FB)KVART) significantly increased binding affinity for integrin αvβ6 (IC50 = 0.021 ± 0.002 µM), binding selectivity for αvβ6-expressing cells (3.1 ± 0.8:1), and the serum stability (>99% stable). Our results demonstrate the challenges in optimizing OBOC-derived peptides, indicate both termini of 1 are sensitive to modifications, and show that further modification of 1 is necessary to demonstrate utility as an 18F-peptide imaging agent.

Original languageEnglish (US)
Article number309
JournalMolecules
Volume24
Issue number2
DOIs
StatePublished - Jan 16 2019

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Keywords

  • Affinity
  • Fluorine-18
  • Integrin αβ
  • Library screening
  • One-bead one-compound (OBOC)
  • Positron emission tomography (PET)
  • Selectivity
  • Solid-phase radiolabeling

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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