Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvβ6/αvβ8 Integrin Ligand

Tomassi, Stefano; D’Amore, Vincenzo Maria; Leva, Francesco Saverio Di; Vannini, Andrea; Quilici, Giacomo; Weinmüller, Michael; Reichart, Florian; Amato, Jussara; Romano, Barbara; Izzo, Angelo A.; Maro, Salvatore Di; Novellino, Ettore; Musco, Giovanna; Gianni, Tatiana; Kessler, Horst; Marinelli, Luciana

doi:10.1021/acs.jmedchem.1c00533

Cited by 10 publications

(12 citation statements)

References 87 publications

(172 reference statements)

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“…Of note, another dual αvβ6/αvβ8 peptide ligand has been recently described (RGD-Chg-( N Me)E]-CONH 2 ) 34 . However, the tumor homing properties of this compound - which inhibits the binding of soluble integrin αvβ6 and αvβ8 to an immobilized ECM protein with an IC 50 of 1.6 and 60 nM, respectively - have not been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

A stapled chromogranin A-derived peptide homes in on tumors that express αvβ6 or αvβ8 integrins

Monieri¹,

Rainone²,

Sacchi³

et al. 2023

Int. J. Biol. Sci.

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Rationale:The αvβ6and αvβ8-integrins, two cell-adhesion receptors upregulated in many tumors and involved in the activation of the latency associated peptide (LAP)/TGFβ complex, represent potential targets for tumor imaging and therapy. We investigated the tumor-homing properties of a chromogranin A-derived peptide containing an RGDL motif followed by a chemically stapled alpha-helix (called "5a"), which selectively recognizes the LAP/TGFβ complex-binding site of αvβ6 and αvβ8. Methods: Peptide 5a was labeled with IRDye 800CW (a near-infrared fluorescent dye) or with 18 F-NOTA (a label for positron emission tomography (PET)); the integrin-binding properties of free peptide and conjugates were then investigated using purified αvβ6/αvβ8 integrins and various αvβ6/αvβ8 single -or double-positive cancer cells; tumor-homing, biodistribution and imaging properties of the conjugates were investigated in subcutaneous and orthotopic αvβ6-positive carcinomas of the pancreas, and in mice bearing subcutaneous αvβ8-positive prostate tumors. Results:In vitro studies showed that 5a can bind both integrins with high affinity and inhibits cell-mediated TGFβ activation. The 5a-IRDye and 5a-NOTA conjugates could bind purified αvβ6/αvβ8 integrins with no loss of affinity compared to free peptide, and selectively recognized various αvβ6/αvβ8 single-or double-positive cancer cells, including cells from pancreatic carcinoma, melanoma, oral mucosa, bladder and prostate cancer. In vivo static and dynamic optical near-infrared and PET/CT imaging and biodistribution studies, performed in mice with subcutaneous and orthotopic αvβ6-positive carcinomas of the pancreas, showed high target-specific uptake of fluorescence-and radio-labeled peptide by tumors and low non-specific uptake in other organs and tissues, except for excretory organs. Significant target-specific uptake of fluorescence-labeled peptide was also observed in mice bearing αvβ8-positive prostate tumors. Conclusions:The results indicate that 5a can home to αvβ6and/or αvβ8-positive tumors, suggesting that this peptide can be exploited as a ligand for delivering imaging or anticancer agents to αvβ6/αvβ8 single-or double-positive tumors, or as a tumor-homing inhibitor of these TGFβ activators.

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Section: Discussionmentioning

confidence: 99%

A stapled chromogranin A-derived peptide homes in on tumors that express αvβ6 or αvβ8 integrins

Monieri¹,

Rainone²,

Sacchi³

et al. 2023

Int. J. Biol. Sci.

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“… 462 , 463 Ebola is related to integrin α5β1, and herpes simplex virus type 1 (HSV-1) interacts with αvβ3. 464 , 465 Moreover, in immunized mice, the increased frequency of circulating integrin α4β7 + cells is correlated with protection against Helicobacter pylori infection. 466 β2 integrin is important in the recruitment of dendritic cells to the infection site and may affect the initiation of innate immunity.…”

Section: Integrin Roles In Physiology and Pathologymentioning

confidence: 99%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

237

111

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Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.

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“…Integrins are cell surface proteins in charge of cell adhesion, cell motility, and bidirectional signaling. , Because of their involvement in wound healing, thrombosis, and cancer cell migration as well as viral entry − and drug delivery, they are of great interest as drug targets . In vertebrates, the integrin superfamily consists of 24 heterodimers, all composed of α and β subunits (Figure A).…”

mentioning

confidence: 99%

Inhibition of Cell Motility by Cell-Penetrating Dynamic Covalent Cascade Exchangers: Integrins Participate in Thiol-Mediated Uptake

Coelho

Saidjalolov

Moreau

et al. 2023

JACS Au

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Integrins are cell surface proteins responsible for cell motility. Inspired by the rich disulfide exchange chemistry of integrins, we show here the inhibition of cell migration by cascade exchangers (CAXs), which also enable and inhibit cell penetration by thiol-mediated uptake. Fast-moving CAXs such as reversible Michael acceptor dimers, dithiabismepanes, and bioinspired epidithiodiketopiperazines are best, much better than Ellman's reagent. The implication that integrins participate in thiol-mediated uptake is confirmed by reduced uptake in integrin-knockdown cells. Although thiol-mediated uptake is increasingly emerging as a unifying pathway to bring matter into cells, its molecular basis is essentially unknown. These results identify the integrin superfamily as experimentally validated general cellular partners in the dynamic covalent exchange cascades that are likely to account for thiolmediated uptake. The patterns identified testify to the complexity of the dynamic covalent networks involved. This work also provides chemistry tools to explore cell motility and expands the drug discovery potential of CAXs from antiviral toward antithrombotic and antitumor perspectives.

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Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvβ6/αvβ8 Integrin Ligand

Cited by 10 publications

References 87 publications

A stapled chromogranin A-derived peptide homes in on tumors that express αvβ6 or αvβ8 integrins

A stapled chromogranin A-derived peptide homes in on tumors that express αvβ6 or αvβ8 integrins

Targeting integrin pathways: mechanisms and advances in therapy

Inhibition of Cell Motility by Cell-Penetrating Dynamic Covalent Cascade Exchangers: Integrins Participate in Thiol-Mediated Uptake

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