α<sub>V</sub>β<sub>6</sub> Integrin: An Intriguing Target for COVID‐19 and Related Diseases

Bugatti, Kelly

doi:10.1002/cbic.202100209

Cited by 9 publications

(5 citation statements)

References 42 publications

(54 reference statements)

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“…αvβ6 integrin has been reported to be of interest in inhibiting SARS-CoV-2 entry and treating coronavirus disease 2019 (COVID-19)-related diseases. 447 SARS-CoV-2 acts on human cells through angiotensin converting enzyme II (ACE2), and recent studies suggested that integrins might be the cell receptors for SARS-CoV-2. 448 The association between the S protein of SARS-CoV-2 and the ACE2 receptor has been established, but the S1 subunit contains a solvent-exposed RGD-binding motif.…”

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

267

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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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

267

111

View full text Add to dashboard Cite

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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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“…[12] Hinting toward thiol-mediated uptake as a unifying network coding for entry, similar, at least partial coincidences can be found for other target candidates (e.g. the transferrin receptor, [10,12] EGFR, [7,10,14] integrins, [7,25] CLIC [7,12] ).…”

mentioning

confidence: 73%

Oligonucleotide Phosphorothioates Enter Cells by Thiol‐Mediated Uptake

et al. 2021

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Oligonucleotide phosphorothioates (OPS) are DNA or RNA mimics where one phosphate oxygen is replaced by a sulfur atom. They have been shown to enter mammalian cells much more efficiently than non‐modified DNA. Thus, solving one of the key challenges with oligonucleotide technology, OPS became very useful in practice, with several FDA‐approved drugs on the market or in late clinical trials. However, the mechanism accounting for this facile cellular uptake is unknown. Here, we show that OPS enter cells by thiol‐mediated uptake. The transient adaptive network produced by dynamic covalent pseudo‐disulfide exchange is characterized in action. Inhibitors with nanomolar efficiency are provided, together with activators that reduce endosomal capture for efficient delivery of OPS into the cytosol, the site of action.

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α_Vβ₆ Integrin: An Intriguing Target for COVID‐19 and Related Diseases

Cited by 9 publications

References 42 publications

Targeting integrin pathways: mechanisms and advances in therapy

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

Oligonucleotide Phosphorothioates Enter Cells by Thiol‐Mediated Uptake

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αVβ6 Integrin: An Intriguing Target for COVID‐19 and Related Diseases

Cited by 9 publications

References 42 publications

Targeting integrin pathways: mechanisms and advances in therapy

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

Oligonucleotide Phosphorothioates Enter Cells by Thiol‐Mediated Uptake

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α_Vβ₆ Integrin: An Intriguing Target for COVID‐19 and Related Diseases