Supramolecular filaments for concurrent ACE2 docking and enzymatic activity silencing enable coronavirus capture and infection prevention

Anderson, Caleb F.; Wang, Qiong; Stern, David; Leonard, Elissa K.; Sun, Boran; Fergie, Kyle J.; Choi, Chang-Yong; Spangler, Jamie B.; Villano, Jason; Pekosz, Andrew; Brayton, Cory; Jia, Hongpeng; Cui, Honggang

doi:10.1016/j.matt.2022.11.027

Cited by 10 publications

(8 citation statements)

References 65 publications

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“…Conventionally, the mixing ratio of co‐assembled peptides plays a critical role in determining the structural features and bioactivity, including optimizing component distribution within the co‐assemblies and maximizing the heterogeneous interaction to promote co‐assembly. For instance, the rational incorporation of ligand peptides into co‐assemblies facilitates the association with cells [63–65] . In our studies, we hypothesize that mixing 25 % RIPK1‐biomimetic peptides with PR3 promotes their heterogeneous interactions, thereby accelerating their co‐assemblies.…”

Section: Resultsmentioning

confidence: 70%

Artificial Peptide‐Protein Necrosomes Promote Cell Death

Guo,

Wang,

Wang

et al. 2023

Angew Chem Int Ed

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The presence of disordered region or large interacting surface within proteins significantly challenges the development of targeted drugs, commonly known as the “undruggable” issue. Here, we report a heterogeneous peptide‐protein assembling strategy to selectively phosphorylate proteins, thereby activating the necroptotic signaling pathway and promoting cell necroptosis. Inspired by the structures of natural necrosomes formed by receptor interacting protein kinases (RIPK) 1 and 3, the kinase‐biomimetic peptides are rationally designed by incorporating natural or D‐amino acids, or connecting D‐amino acids in a retro‐inverso (DRI) manner, leading to one RIPK3‐biomimetic peptide PR3 and three RIPK1‐biomimetic peptides. Individual peptides undergo self‐assembly into nanofibrils, whereas mixing RIPK1‐biomimetic peptides with PR3 accelerates and enhances assembly of PR3. In particular, RIPK1‐biomimetic peptide DRI‐PR1 exhibits reliable binding affinity with protein RIPK3, resulting in specific cytotoxicity to colon cancer cells that overexpress RIPK3. Mechanistic studies reveal the increased phosphorylation of RIPK3 induced by RIPK1‐biomimetic peptides, elucidating the activation of the necroptotic signaling pathway responsible for cell death without an obvious increase in secretion of inflammatory cytokines. Our findings highlight the potential of peptide‐protein hybrid aggregation as a promising approach to address the “undruggable” issue and provide alternative strategies for overcoming cancer resistance in the future.

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Section: Resultsmentioning

confidence: 70%

Artificial Peptide‐Protein Necrosomes Promote Cell Death

Guo,

Wang,

Wang

et al. 2023

Angew Chem Int Ed

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“…Furthermore, co-assembly of the bioactive PA molecule with a non-bioactive diluent at different molar ratios allowed us to optimize the epitope density on nanofiber surfaces for bioactivity and also the chemical stability of the active peptide. As peptide-based nanofibers, these ACE2-mimicking supramolecular assemblies have great potential for further development in clinical applications such as delivery through the respiratory system as a nasal spray. , Our work suggests that the supramolecular presentation of bioactive sequences by PA nanofibers can offer opportunities to develop effective strategies to prevent viral infections..…”

Section: Discussionmentioning

confidence: 83%

“…As peptide-based nanofibers, these ACE2-mimicking supramolecular assemblies have great potential for further development in clinical applications such as delivery through the respiratory system as a nasal spray. 43,44 Our work suggests that the supramolecular presentation of bioactive sequences by PA nanofibers can offer opportunities to develop effective strategies to prevent viral infections..…”

Section: ■ Conclusionmentioning

confidence: 94%

Supramolecular Nanofibers Block SARS-CoV-2 Entry into Human Host Cells

Qiu

Chen

Álvarez

et al. 2023

ACS Appl. Mater. Interfaces

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) on host cells to initiate cellular entry. Blocking the interactions between the spike protein and ACE2 offers promising therapeutic opportunities to prevent infection. We report here on peptide amphiphile supramolecular nanofibers that display a sequence from ACE2 in order to promote interactions with the SARS-CoV-2 spike receptor binding domain. We demonstrate that displaying this sequence on the surface of supramolecular assemblies preserves its α-helical conformation and blocks the entry of a pseudovirus and its two variants into human host cells. We also found that the chemical stability of the bioactive structures was enhanced in the supramolecular environment relative to the unassembled peptide molecules. These findings reveal unique advantages of supramolecular peptide therapies to prevent viral infections and more broadly for other targets as well.

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“…SARS-CoV-2 S protein gene expressing cDNA (gift from Dr. Marc Johnson, University of Missouri School of Medicine) was used to pseudotype Feline immunodeficiency virus (FIV) expressing luciferase (ScV2 S-FIV-mCherry/Luc) or green fluorescent protein (ScV2 S-FIV-GFP) by using previously described methods (18,19).…”

Section: Production Of Luciferase-and Gfp-tagged Pseudotyped Particlesmentioning

confidence: 99%

“…Nearly 7 million people have died due to coronavirus disease 2019 (COVID- 19), with the United States reporting more deaths than any other country. COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1).…”

Section: Introductionmentioning

confidence: 99%

Human Surfactant Protein A Alleviates SARS-CoV-2 Infectivity in Human Lung Epithelial Cells

Jacob

Gemmiti

Xiong

et al. 2023

Preprint

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SARS coronavirus 2 (SARS-CoV-2) infects human angiotensin-converting enzyme 2 (hACE2)-expressing lung epithelial cells through its spike (S) protein. The S protein is highly glycosylated and could be a target for lectins. Surfactant protein A (SP-A) is a collagen-containing C-type lectin, expressed by mucosal epithelial cells and mediates its antiviral activities by binding to viral glycoproteins. This study examined the mechanistic role of human SP-A in SARS-CoV-2 infectivity. The interactions between human SP-A and SARS-CoV-2 S protein and hACE2 receptor, and SP-A level in COVID-19 patients were assessed by ELISA. The effect of SP-A on SARS-CoV-2 infectivity was analyzed by infecting human lung epithelial cells (A549-ACE2) with pseudoviral particles and infectious SARS-CoV-2 (Delta variant) pre-incubated with SP-A. Virus binding, entry, and infectivity were assessed by RT-qPCR, immunoblotting, and plaque assay. The results showed that human SP-A can bind SARS-CoV-2 S protein/RBD and hACE2 in a dose-dependent manner (p<0.01). Human SP-A inhibited virus binding and entry, and reduce viral load in lung epithelial cells, evidenced by the dose-dependent decrease in viral RNA, nucleocapsid protein, and titer (p<0.01). Increased SP-A level was observed in the saliva of COVID-19 patients compared to healthy controls (p<0.05), but severe COVID-19 patients had relatively lower SP-A levels than moderate COVID-19 patients (p<0.05). Therefore, SP-A plays an important role in mucosal innate immunity against SARS-CoV-2 infectivity by directly binding to the S protein and inhibiting its infectivity in host cells. SP-A level in the saliva of COVID-19 patients might serve as a biomarker for COVID-19 severity.

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Supramolecular filaments for concurrent ACE2 docking and enzymatic activity silencing enable coronavirus capture and infection prevention

Cited by 10 publications

References 65 publications

Artificial Peptide‐Protein Necrosomes Promote Cell Death

Artificial Peptide‐Protein Necrosomes Promote Cell Death

Supramolecular Nanofibers Block SARS-CoV-2 Entry into Human Host Cells

Human Surfactant Protein A Alleviates SARS-CoV-2 Infectivity in Human Lung Epithelial Cells

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