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The Integrin Binding Peptide, ATN-161, as a Novel Therapy for SARS-CoV-2 Infection.

ABSTRACT: Many efforts to design and screen therapeutics for the current severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic have focused on inhibiting viral host cell entry by disrupting ACE2 binding with the SARS-CoV-2 spike protein. This work focuses on the potential to inhibit SARS-CoV-2 entry through a hypothesized ?5?1integrin-based mechanism, and indicates that inhibiting ?5?1 integrin interaction with ACE2 and the spike protein using a novel molecule ATN-161 represents a promising approach to treat COVID-19.

SUBMITTER: Beddingfield B

PROVIDER: S-EPMC7310614 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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The Integrin Binding Peptide, ATN-161, as a Novel Therapy for SARS-CoV-2 Infection.

Beddingfield Brandon B Iwanaga Naoki N Chapagain Prem P Zheng Wenshu W Roy Chad J CJ Hu Tony Y TY Kolls Jay J Bix Gregory G

bioRxiv : the preprint server for biology 20200724

Many efforts to design and screen therapeutics for severe acute respiratory syndrome coronavirus (SARS-CoV-2) have focused on inhibiting viral cell entry by disrupting ACE2 binding with the SARS-CoV-2 spike protein. This work focuses on inhibiting SARS-CoV-2 entry through a hypothesized α5β1 integrin-based mechanism, and indicates that inhibiting the spike protein interaction with α5β1 integrin (+/- ACE2), and the interaction between α5β1 integrin and ACE2 using a molecule ATN-161 represents a p ...[more]

PMID: 32587959

Similar Datasets

The Integrin Binding Peptide, ATN-161, as a Novel Therapy for SARS-CoV-2 Infection.

Project description:Many efforts to design and screen therapeutics for the current severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic have focused on inhibiting viral host cell entry by disrupting angiotensin-converting enzyme-2 (ACE2) binding with the SARS-CoV-2 spike protein. This work focuses on the potential to inhibit SARS-CoV-2 entry through a hypothesized α5β1 integrin-based mechanism and indicates that inhibiting the spike protein interaction with α5β1 integrin (+/- ACE2) and the interaction between α5β1 integrin and ACE2 using a novel molecule (ATN-161) represents a promising approach to treat coronavirus disease-19.

| S-EPMC7566794 | biostudies-literature

Penta-peptide ATN-161 based neutralization mechanism of SARS-CoV-2 spike protein.

Project description:SARS-CoV-2 has become a big challenge for the scientific community worldwide. SARS-CoV-2 enters into the host cell by the spike protein binding with an ACE2 receptor present on the host cell. Developing safe and effective inhibitor appears an urgent need to interrupt the binding of SARS-CoV-2 spike protein with ACE2 receptor in order to reduce the SARS-CoV-2 infection. We have examined the penta-peptide ATN-161 as potential inhibitor of ACE2 and SARS-CoV-2 spike protein binding, where ATN-161 has been commercially approved for the safety and possess high affinity and specificity towards the receptor binding domain (RBD) of S1 subunit in SARS-CoV-2 spike protein. We carried out experiments and confirmed these phenomena that the virus bindings were indeed minimized. ATN-161 peptide can be used as an inhibitor of protein-protein interaction (PPI) stands as a crucial interaction in biological systems. The molecular docking finding suggests that the binding energy of the ACE2-spike protein complex is reduced in the presence of ATN-161. Protein-protein docking binding energy (-40.50 kcal/mol) of the spike glycoprotein toward the human ACE2 and binding of ATN-161 at their binding interface reduced the biding energy (-26.25 kcal/mol). The finding of this study suggests that ATN-161 peptide can mask the RBD of the spike protein and be considered as a neutralizing candidate by binding with the ACE2 receptor. Peptide-based masking of spike S1 protein (RBD) and its neutralization is a highly promising strategy to prevent virus penetration into the host cell. Thus masking of the RBD leads to the loss of receptor recognition property which can reduce the chance of infection host cells.

| S-EPMC8578017 | biostudies-literature

In Vivo protection from SARS-CoV-2 infection by ATN-161 in k18-hACE2 transgenic mice.

Project description: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 α5β1, and human ACE2 to facilitate viral entry into host cells in vitro. We previously found that inhibition of integrin α5β1 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 h 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 h post-infection. Furthermore, ATN-161 reduced SARS-CoV-2-induced increased expression of lung integrin α5 and αv (an α5-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 α5β1 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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Control of complement-induced inflammatory responses to SARS-CoV-2 infection by anti-SARS-CoV-2 antibodies

Project description:Dysregulated immune responses contribute to the excessive and uncontrolled inflammation observed in severe COVID-19. However, how immunity to SARS-CoV-2 is induced and regulated remains unclear. Here we uncover a role of the complement system in the induction of innate and adaptive immunity to SARS-CoV-2. Complement rapidly opsonizes SARS-CoV-2 particles via the lectin pathway. Complement-opsonized SARS-CoV-2 efficiently induces type-I interferon and pro-inflammatory cytokine responses via activation of dendritic cells, which are inhibited by antibodies against the complement receptors (CR) 3 and 4. Serum from COVID-19 patients, or monoclonal antibodies against SARS-CoV-2, attenuate innate and adaptive immunity induced by complement-opsonized SARS-CoV-2. Blocking of CD32, the FcγRII antibody receptor of dendritic cells, restores complement-induced immunity. These results suggest that opsonization of SARS-CoV-2 by complement is involved in the induction of innate and adaptive immunity to SARS-CoV-2 in the acute phase of infection. Subsequent antibody responses limit inflammation and restore immune homeostasis. These findings suggest that dysregulation of the complement system and FcγRII signaling may contribute to severe COVID-19.

| S-SCDT-10_1038-S44318-024-00061-0 | biostudies-other

A Retrospective Cohort Study for Main Postoperative Complications After SARS-CoV-2 Infection

Project description:To explore the relationship between SARS-CoV-2 infection in different time before operation and postoperative main complications (mortality, main pulmonary and cardiovascular complications) 30 days after operation; To determine the best timing of surgery after SARS-CoV-2 infection.

| 12454 | ecrin-mdr-crc

Integrin activation is an essential component of SARS-CoV-2 infection.

Project description:SARS-CoV-2 infection depends on binding its spike (S) protein to angiotensin-converting enzyme 2 (ACE2). The S protein expresses an RGD motif, suggesting that integrins may be co-receptors. Here, we UV-inactivated SARS-CoV-2 and fluorescently labeled the envelope membrane with octadecyl rhodamine B (R18) to explore the role of integrin activation in mediating cell entry and productive infection. We used flow cytometry and confocal microscopy to show that SARS-CoV-2R18 particles engage basal-state integrins. Furthermore, we demonstrate that Mn2+, which induces integrin extension, enhances cell entry of SARS-CoV-2R18. We also show that one class of integrin antagonist, which binds to the αI MIDAS site and stabilizes the inactive, closed conformation, selectively inhibits the engagement of SARS-CoV-2R18 with basal state integrins, but is ineffective against Mn2+-activated integrins. RGD-integrin antagonists inhibited SARS-CoV-2R18 binding regardless of integrin activation status. Integrins transmit signals bidirectionally: 'inside-out' signaling primes the ligand-binding function of integrins via a talin-dependent mechanism, and 'outside-in' signaling occurs downstream of integrin binding to macromolecular ligands. Outside-in signaling is mediated by Gα13. Using cell-permeable peptide inhibitors of talin and Gα13 binding to the cytoplasmic tail of an integrin's β subunit, we demonstrate that talin-mediated signaling is essential for productive infection.

| S-EPMC8516859 | biostudies-literature

SHAE002: SARS-CoV, SARS-dORF6 and SARS-BatSRBD infection of HAE cultures.

Project description:HAE cultures were infected with SARS-CoV, SARS-dORF6 or SARS-BatSRBD and were directly compared to A/CA/04/2009 H1N1 influenza-infected cultures. Cell samples were collected at various hours post-infection for analysis. Time Points = 0, 12, 24, 36, 48, 60, 72, 84 and 96 hrs post-infection for SARS-CoV, SARS-dORF6 and SARS-BatSRBD. Time Points = 0, 6, 12, 18, 24, 36 and 48 hrs post-infection for H1N1. Done in triplicate or quadruplicate for RNA Triplicates/quadruplicates are defined as 3/4 different wells, plated at the same time and using the same cell stock for all replicates. Time matched mocks done in triplicate from same cell stock as rest of samples. Culture medium (the same as what the virus stock is in) will be used for the mock infections. Infection was done at an MOI of 2.

2013-07-31 | E-GEOD-47960 | biostudies-arrayexpress

SHAE003: SARS-CoV, SARS-dORF6 and SARS-BatSRBD infection of HAE cultures.

Project description:HAE cultures were infected with SARS-CoV, SARS-ddORF6 or SARS-BatSRBD and were directly compared to A/CA/04/2009 H1N1 influenza-infected cultures. Cell samples were collected at various hours post-infection for analysis. Time Points = 0, 12, 24, 36, 48, 60, 72, 84 and 96 hrs post-infection for SARS-CoV. Time Points = 0, 24, 48, 60, 72, 84 and 96 hrs post-infection forSARS-ddORF6 and SARS-BatSRBD. Time Points = 0, 6, 12, 18, 24, 36 and 48 hrs post-infection for H1N1. Done in triplicate/quadruplicate for RNA Triplicates/quadruplicates are defined as 3/4 different wells, plated at the same time and using the same cell stock for all replicates. Time matched mocks done in triplicate from same cell stock as rest of samples. Culture medium (the same as what the virus stock is in) will be used for the mock infections. Infection was done at an MOI of 2.

2013-07-31 | E-GEOD-47961 | biostudies-arrayexpress

SHAE004: SARS-CoV, SARS-dORF6 and SARS-BatSRBD infection of HAE cultures.

Project description:HAE cultures were infected with SARS-CoV, SARS-dORF6 or SARS-BatSRBD and were directly compared to A/CA/04/2009 H1N1 influenza-infected cultures. Cell samples were collected at various hours post-infection for analysis. Time Points = 0, 12, 24, 36, 48, 60, 72, 84 and 96 hrs post-infection for SARS-CoV, SARS-dORF6 and SARS-BatSRBD. Time Points = 0, 6, 12, 18, 24, 36 and 48 hrs post-infection for H1N1. Done in triplicate for RNA Triplicates are defined as 3 different wells, plated at the same time and using the same cell stock for all replicates. Time matched mocks done in triplicate from same cell stock as rest of samples. Culture medium (the same as what the virus stock is in) will be used for the mock infections. Infection was done at an MOI of 2 for SARS viruses and an MOI of 1 for H1N1.

2013-07-31 | E-GEOD-47962 | biostudies-arrayexpress

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