Integrins as Therapeutic Targets for SARS-CoV-2

Gressett, Timothy E.; Nader, Danielle; Robles, Juan Pablo; Buranda, Tione; Kerrigan, Steven W.; Bix, Gregory

doi:10.3389/fcimb.2022.892323

Cited by 13 publications

(8 citation statements)

References 30 publications

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“…The investigation of potential non-RGD-based interactions between integrins and SARS-CoV-2 subvariant spike proteins remains warranted [ 21 , 32 ]. These findings re-emphasize the relevance of integrin-based therapies for SARS-CoV-2 and other viral infections [ 9 , 33 , 34 ]. Monitoring of mutations and their potential impacts on protein-protein interactions may reveal novel insights into viral pathogenesis and tropism [ 35 ].…”

Section: Discussionsupporting

confidence: 54%

SARS-CoV-2 Omicron subvariant spike N405 unlikely to rapidly deamidate

Beaudoin

Petsolari

Hamaia

et al. 2023

Biochemical and Biophysical Research Communications

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Section: Discussionsupporting

confidence: 54%

SARS-CoV-2 Omicron subvariant spike N405 unlikely to rapidly deamidate

Beaudoin

Petsolari

Hamaia

et al. 2023

Biochemical and Biophysical Research Communications

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“…Recent studies have shown that SLiM-based peptide inhibitors and drugs such as nutlin, venetoclax and cilengitide can reduce the infectivity of many viruses. However, the broad spectrum antiviral capability of these therapeutic strategies remain to be explored [ 74 , 75 ]. Thus, elucidating the structural and molecular basis of the interactions of viral SLiMs with host cell surface receptors can help us to design newer intervention techniques against viral infections in future.…”

Section: Discussionmentioning

confidence: 99%

Molecular mimicry of host short linear motif-mediated interactions utilised by viruses for entry

2023

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Viruses are obligate intracellular parasites that depend on host cellular machinery for performing even basic biological functions. One of the many ways they achieve this is through molecular mimicry, wherein the virus mimics a host sequence or structure, thereby being able to hijack the host's physiological interactions for its pathogenesis. Such adaptations are specific recognitions that often confer tissue and species-specific tropisms to the virus, and enable the virus to utilise previously existing host signalling networks, which ultimately aid in further steps of viral infection, such as entry, immune evasion and spread. A common form of sequence mimicry utilises short linear motifs (SLiMs). SLiMs are short-peptide sequences that mediate transient interactions and are major elements in host protein interaction networks. This work is aimed at providing a comprehensive review of current literature of some well-characterised SLiMs that play a role in the attachment and entry of viruses into host cells, which mimic physiological receptor-ligand interactions already present in the host. Considering recent trends in emerging diseases, further research on such motifs involved in viral entry can help in the discovery of previously unknown cellular receptors utilised by viruses, as well as help in the designing of targeted therapeutics such as vaccines or inhibitors directed towards these interactions.

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“…However, both antibodies were sensitive to mutations found in circulating variants of concern B.1.351 and B.1.617.2, and B.1.1.529 was partially or completely resistant to 100% of neutralizing monoclonal antibodies [ 16 ]. The RGD (403–405) motif is located within the spike receptor-binding domain and is conserved across >99% of variants [ 17 ]. As vaccine and immune-induced immunity is a key contributor to viral evolution, developing a compound that targets less immunodominant epitopes such as the RGD motif could be a more effective strategy against SARS-CoV-2 variants.…”

Section: Discussionmentioning

confidence: 99%

Molecular Cross-Talk between Integrins and Cadherins Leads to a Loss of Vascular Barrier Integrity during SARS-CoV-2 Infection

Nader

Kerrigan

2022

Viruses

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The vascular barrier is heavily injured following SARS-CoV-2 infection and contributes enormously to life-threatening complications in COVID-19. This endothelial dysfunction is associated with the phlogistic phenomenon of cytokine storms, thrombotic complications, abnormal coagulation, hypoxemia, and multiple organ failure. The mechanisms surrounding COVID-19 associated endotheliitis have been widely attributed to ACE2-mediated pathways. However, integrins are emerging as possible receptor candidates for SARS-CoV-2, and their complex intracellular signaling events are essential for maintaining endothelial homeostasis. Here, we showed that the spike protein of SARS-CoV-2 depends on its RGD motif to drive barrier dysregulation by hijacking integrin αVβ3, expressed on human endothelial cells. This triggers the redistribution and internalization of major junction protein VE-Cadherin which leads to the barrier disruption phenotype. Both extracellular and intracellular inhibitors of integrin αVβ3 prevented these effects, similarly to the RGD-cyclic peptide compound Cilengitide, which suggests that the spike protein—through its RGD motif—binds to αVβ3 and elicits vascular leakage events. These findings support integrins as an additional receptor for SARS-CoV-2, particularly as integrin engagement can elucidate many of the adverse endothelial dysfunction events that stem from COVID-19.

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Integrins as Therapeutic Targets for SARS-CoV-2

Cited by 13 publications

References 30 publications

SARS-CoV-2 Omicron subvariant spike N405 unlikely to rapidly deamidate

SARS-CoV-2 Omicron subvariant spike N405 unlikely to rapidly deamidate

Molecular mimicry of host short linear motif-mediated interactions utilised by viruses for entry

Molecular Cross-Talk between Integrins and Cadherins Leads to a Loss of Vascular Barrier Integrity during SARS-CoV-2 Infection

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