RGD‐binding integrins and TGF‐β in SARS‐CoV‐2 infections – novel targets to treat COVID‐19 patients?

Carvacho, Ingrid; Piesche, Matthias

doi:10.1002/cti2.1240

Cited by 36 publications

(39 citation statements)

References 179 publications

(345 reference statements)

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“…Integrins are cell-surface transmembrane receptors responsible for platelet aggregation, cell adhesion, cell migration, and cell-signalling processes [23]. Since the RGD motif is close to the ACE2 receptor-binding region of the S1 subunit, integrin may act as co-receptor that could increase the binding potency of ACE2 for SARS-CoV-2 (Figure 1C), explaining the fast spread and aggressiveness of the virus [115]. On the other hand, integrin may act as an alternative receptor for SARS-CoV-2 and could expand cell tropism and potentially affect the viral pathogenicity and spread.…”

Section: Integrinsmentioning

confidence: 99%

The Fight against COVID-19 on the Multi-Protease Front and Surroundings: Could an Early Therapeutic Approach with Repositioning Drugs Prevent the Disease Severity?

et al. 2021

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The interaction between the membrane spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the transmembrane angiotensin-converting enzyme 2 (ACE2) receptor of the human epithelial host cell is the first step of infection, which has a critical role for viral pathogenesis of the current coronavirus disease-2019 (COVID-19) pandemic. Following the binding between S1 subunit and ACE2 receptor, different serine proteases, including TMPRSS2 and furin, trigger and participate in the fusion of the viral envelope with the host cell membrane. On the basis of the high virulence and pathogenicity of SARS-CoV-2, other receptors have been found involved for viral binding and invasiveness of host cells. This review comprehensively discusses the mechanisms underlying the binding of SARS-CoV2 to ACE2 and putative alternative receptors, and the role of potential co-receptors and proteases in the early stages of SARS-CoV-2 infection. Given the short therapeutic time window within which to act to avoid the devastating evolution of the disease, we focused on potential therapeutic treatments—selected mainly among repurposing drugs—able to counteract the invasive front of proteases and mild inflammatory conditions, in order to prevent severe infection. Using existing approved drugs has the advantage of rapidly proceeding to clinical trials, low cost and, consequently, immediate and worldwide availability.

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Section: Integrinsmentioning

confidence: 99%

The Fight against COVID-19 on the Multi-Protease Front and Surroundings: Could an Early Therapeutic Approach with Repositioning Drugs Prevent the Disease Severity?

et al. 2021

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“…Most of the former works have relied on sequence conservation and motif detection analysis to conclude on the implication of RGD motif in SARS-CoV-2 RBD in the interaction with integrins [14,18,36,50]. However, few of them have considered the structural features to reinforce or confirm the hypothesis with details, as presented in this study.…”

mentioning

confidence: 94%

SARS-CoV-2 spike protein unlikely to bind to integrins via the Arg-Gly-Asp (RGD) motif of the Receptor Binding Domain: evidence from structural analysis and microscale accelerated molecular dynamics

Othman¹,

Messaoud

Khamessi

et al. 2021

Preprint

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The Receptor Binding Domain (RBD) of SARS-CoV-2 virus harbors a sequence of Arg-Gly-Asp tripeptide named RGD motif, which has also been identified in extracellular matrix proteins that bind integrins as well as other disintegrins and viruses. Accordingly, integrins have been proposed as host receptors for SARS-CoV-2. The hypothesis was supported by sequence and structural analysis. However, given that the microenvironment of the RGD motif imposes structural hindrance to the protein-protein association, the validity of this hypothesis is still uncertain. Here, we used normal mode analysis, accelerated molecular dynamics microscale simulation, and protein-protein docking to investigate the putative role of RGD motif of SARS-CoV-2 RBD for interacting with integrins. We found, by molecular dynamics, that neither RGD motif nore its microenvironment show any significant conformational shift in the RBD structure. Highly populated clusters were used to run a protein-protein docking against three RGD-binding integrin types, showing no capability of the RBD domain to interact with the RGD binding site. Moreover, the free energy landscape revealed that the RGD conformation within RBD could not acquire an optimal geometry to allow the interaction with integrins. Our results highlighted different structural features of the RGD motif that may prevent its involvement in the interaction with integrins. We, therefore, suggest, in the case where integrins are confirmed to be the direct host receptors for SARS-CoV-2, a possible involvement of other residues to stabilize the interaction.

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“…Importantly, the β 1 family of integrins are closely associated with ACE2 [24]. A recent study reviewed novel mutation (K403R) in the spike protein that does not exist in other strains of the coronavirus, creating an RGD motif, which could be recognized by integrins [2]. Therefore, the new RGD motif in SARS-CoV-2 could increase the binding potency of ACE2-positive target cells in association with β 1 integrins as well as potentially facilitating infection of ACE2-negative cells [2].…”

Section: Introductionmentioning

confidence: 99%

“…A recent study reviewed novel mutation (K403R) in the spike protein that does not exist in other strains of the coronavirus, creating an RGD motif, which could be recognized by integrins [2]. Therefore, the new RGD motif in SARS-CoV-2 could increase the binding potency of ACE2-positive target cells in association with β 1 integrins as well as potentially facilitating infection of ACE2-negative cells [2]. This could help explain the faster and aggressive spread of virus as compared to SARS-CoV-1, which belongs to the same family of betacoronaviruses [25].…”

Section: Introductionmentioning

confidence: 99%

“…Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent causative of coronavirus disease 2019 (COVID- 19), is a highly transmissible respiratory pathogen in which an estimated 14% of all patients will develop serious conditions, with a subsequent mortality rate of 1.4 -3.4% [1][2][3]. Several non-pharmacological interventions have been implemented to slow down the spread of SARS-CoV-2 [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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In-vivo Protection from SARS-CoV-2 infection by ATN-161 in k18-hACE2 transgenic mice

Amruta¹,

Engler-Chiurazzi

Murray-Brown³

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an infectious disease that has spread worldwide. Current treatments are limited in both availability and efficacy, such that improving our understanding of the factors that facilitate infection is urgently needed to more effectively treat infected individuals and to curb the pandemic. We and others have previously demonstrated the significance of interactions between the SARS-CoV-2 spike protein, integrin alpha5beta1 and human ACE2 to facilitate viral entry into host cells in vitro. We previously found that inhibition of integrin alpha5beta1 by the clinically validated small peptide ATN-161 inhibits these spike protein interactions and cell infection in vitro. In continuation with our previous findings, here we have further evaluated the therapeutic potential of ATN-161 on SARS-CoV-2 infection in k18-hACE2 transgenic (SARS-CoV-2 susceptible) mice in vivo. We discovered that treatment with single- or repeated intravenous doses of ATN-161 (1 mg/kg) within 48 hours after intranasal inoculation with SARS-CoV-2 lead to a reduction of lung viral load, viral immunofluorescence and improved lung histology in a majority of mice 72 hours post-infection. Furthermore, ATN-161 reduced SARS-CoV-2-induced increased expression of lung integrin alpha 5 and alpha v (an alpha 5-related integrin that has also been implicated in SARS-CoV-2 interactions) as well as the C-X-C motif chemokine ligand 10 (Cxcl10), further supporting the potential involvement of these integrins, and the anti-inflammatory potential of ATN-161, respectively, in SARS-CoV-2 infection. To the best of our knowledge, this is the first study demonstrating the potential therapeutic efficacy of targeting integrin alpha5beta1 in SARS-CoV-2 infection in vivo and supports the development of ATN-161 as a novel SARS-CoV-2 therapy.

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RGD‐binding integrins and TGF‐β in SARS‐CoV‐2 infections – novel targets to treat COVID‐19 patients?

Cited by 36 publications

References 179 publications

The Fight against COVID-19 on the Multi-Protease Front and Surroundings: Could an Early Therapeutic Approach with Repositioning Drugs Prevent the Disease Severity?

The Fight against COVID-19 on the Multi-Protease Front and Surroundings: Could an Early Therapeutic Approach with Repositioning Drugs Prevent the Disease Severity?

SARS-CoV-2 spike protein unlikely to bind to integrins via the Arg-Gly-Asp (RGD) motif of the Receptor Binding Domain: evidence from structural analysis and microscale accelerated molecular dynamics

In-vivo Protection from SARS-CoV-2 infection by ATN-161 in k18-hACE2 transgenic mice

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