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

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

Fingerprint

Positron emission tomography
Integrins
beads
Positron-Emission Tomography
Libraries
peptides
positrons
tomography
Imaging techniques
Peptides
optimization
Inhibitory Concentration 50
serums
affinity
Peptide Library
Serum
cells
Assays
Screening
Color

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

Cite this

@article{4e437876cf694c59a6ca5aae5c7bfc9a,
title = "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",
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.",
keywords = "Affinity, Fluorine-18, Integrin αβ, Library screening, One-bead one-compound (OBOC), Positron emission tomography (PET), Selectivity, Solid-phase radiolabeling",
author = "Tang, {Yng C.} and Davis, {Ryan A.} and Tanushree Ganguly and Julie Sutcliffe",
year = "2019",
month = "1",
day = "16",
doi = "10.3390/molecules24020309",
language = "English (US)",
volume = "24",
journal = "Molecules",
issn = "1420-3049",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
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T1 - Identification, Characterization, and Optimization of Integrin αvβ6-Targeting Peptides from a One-Bead One-Compound (OBOC) Library

T2 - Towards the development of positron emission tomography (PET) imaging agents

AU - Tang, Yng C.

AU - Davis, Ryan A.

AU - Ganguly, Tanushree

AU - Sutcliffe, Julie

PY - 2019/1/16

Y1 - 2019/1/16

N2 - 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.

AB - 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.

KW - Affinity

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KW - Library screening

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KW - Positron emission tomography (PET)

KW - Selectivity

KW - Solid-phase radiolabeling

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M3 - Article

VL - 24

JO - Molecules

JF - Molecules

SN - 1420-3049

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M1 - 309

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