Succinimide-Based Conjugates Improve IsoDGR Cyclopeptide Affinity to αvβ3 without Promoting Integrin Allosteric Activation

F Nardelli, C Paissoni, G Quilici, A Gori, C Traversari, B Valentinis, A Sacchi, A Corti, F Curnis, M Ghitti, G Musco

Research output: Contribution to journalArticle

Abstract

The isoDGR sequence is an integrin-binding motif that has been successfully employed as a tumor-vasculature-homing molecule or for the targeted delivery of drugs and diagnostic agents to tumors. In this context, we previously demonstrated that cyclopeptide 2, the product of the conjugation of c(CGisoDGRG) (1) to 4-( N-maleimidomethyl)cyclohexane-1-carboxamide, can be successfully used as a tumor-homing ligand for nanodrug delivery to neoplastic tissues. Here, combining NMR, computational, and biochemical methods, we show that the succinimide ring contained in 2 contributes to stabilizing interactions with αvβ3, an integrin overexpressed in the tumor vasculature. Furthermore, we demonstrate that various cyclopeptides containing the isoDGR sequence embedded in different molecular scaffolds do not induce αvβ3 allosteric activation and work as pure integrin antagonists. These results could be profitably exploited for the rational design of novel isoDGR-based ligands and tumor-targeting molecules with improved αvβ3-binding properties and devoid of adverse integrin-activating effects.
Original languageEnglish
Pages (from-to)7474-7485
Number of pages12
JournalJournal of Medicinal Chemistry
Volume61
Issue number17
DOIs
Publication statusPublished - 2018

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Cyclic Peptides
Integrins
Neoplasms
Ligands
succinimide
Pharmaceutical Preparations

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@article{246f946c6b39460387ed72330dd01cee,
title = "Succinimide-Based Conjugates Improve IsoDGR Cyclopeptide Affinity to αvβ3 without Promoting Integrin Allosteric Activation",
abstract = "The isoDGR sequence is an integrin-binding motif that has been successfully employed as a tumor-vasculature-homing molecule or for the targeted delivery of drugs and diagnostic agents to tumors. In this context, we previously demonstrated that cyclopeptide 2, the product of the conjugation of c(CGisoDGRG) (1) to 4-( N-maleimidomethyl)cyclohexane-1-carboxamide, can be successfully used as a tumor-homing ligand for nanodrug delivery to neoplastic tissues. Here, combining NMR, computational, and biochemical methods, we show that the succinimide ring contained in 2 contributes to stabilizing interactions with αvβ3, an integrin overexpressed in the tumor vasculature. Furthermore, we demonstrate that various cyclopeptides containing the isoDGR sequence embedded in different molecular scaffolds do not induce αvβ3 allosteric activation and work as pure integrin antagonists. These results could be profitably exploited for the rational design of novel isoDGR-based ligands and tumor-targeting molecules with improved αvβ3-binding properties and devoid of adverse integrin-activating effects.",
author = "F Nardelli and C Paissoni and G Quilici and A Gori and C Traversari and B Valentinis and A Sacchi and A Corti and F Curnis and M Ghitti and G Musco",
year = "2018",
doi = "10.1021/acs.jmedchem.8b00745",
language = "English",
volume = "61",
pages = "7474--7485",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "17",

}

TY - JOUR

T1 - Succinimide-Based Conjugates Improve IsoDGR Cyclopeptide Affinity to αvβ3 without Promoting Integrin Allosteric Activation

AU - Nardelli, F

AU - Paissoni, C

AU - Quilici, G

AU - Gori, A

AU - Traversari, C

AU - Valentinis, B

AU - Sacchi, A

AU - Corti, A

AU - Curnis, F

AU - Ghitti, M

AU - Musco, G

PY - 2018

Y1 - 2018

N2 - The isoDGR sequence is an integrin-binding motif that has been successfully employed as a tumor-vasculature-homing molecule or for the targeted delivery of drugs and diagnostic agents to tumors. In this context, we previously demonstrated that cyclopeptide 2, the product of the conjugation of c(CGisoDGRG) (1) to 4-( N-maleimidomethyl)cyclohexane-1-carboxamide, can be successfully used as a tumor-homing ligand for nanodrug delivery to neoplastic tissues. Here, combining NMR, computational, and biochemical methods, we show that the succinimide ring contained in 2 contributes to stabilizing interactions with αvβ3, an integrin overexpressed in the tumor vasculature. Furthermore, we demonstrate that various cyclopeptides containing the isoDGR sequence embedded in different molecular scaffolds do not induce αvβ3 allosteric activation and work as pure integrin antagonists. These results could be profitably exploited for the rational design of novel isoDGR-based ligands and tumor-targeting molecules with improved αvβ3-binding properties and devoid of adverse integrin-activating effects.

AB - The isoDGR sequence is an integrin-binding motif that has been successfully employed as a tumor-vasculature-homing molecule or for the targeted delivery of drugs and diagnostic agents to tumors. In this context, we previously demonstrated that cyclopeptide 2, the product of the conjugation of c(CGisoDGRG) (1) to 4-( N-maleimidomethyl)cyclohexane-1-carboxamide, can be successfully used as a tumor-homing ligand for nanodrug delivery to neoplastic tissues. Here, combining NMR, computational, and biochemical methods, we show that the succinimide ring contained in 2 contributes to stabilizing interactions with αvβ3, an integrin overexpressed in the tumor vasculature. Furthermore, we demonstrate that various cyclopeptides containing the isoDGR sequence embedded in different molecular scaffolds do not induce αvβ3 allosteric activation and work as pure integrin antagonists. These results could be profitably exploited for the rational design of novel isoDGR-based ligands and tumor-targeting molecules with improved αvβ3-binding properties and devoid of adverse integrin-activating effects.

U2 - 10.1021/acs.jmedchem.8b00745

DO - 10.1021/acs.jmedchem.8b00745

M3 - Article

VL - 61

SP - 7474

EP - 7485

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 17

ER -