Engineering a Novel Antibody-Peptide Bispecific Fusion Protein Against MERS-CoV

Wang, Lili; Xu, Jiyan; Yu, Ker‐Wei; Liang, Ruiying; Li, Wei; Li, Jinyao; Lu, Jun; Dimitrov, Dimiter S.; Yu, Fei; Wu, Yanling; Ying, Tianlei

doi:10.3390/antib8040053

Cited by 11 publications

(9 citation statements)

References 55 publications

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“…Never-the-less, huge efforts are on-going to develop vaccines and antibody-based therapies based on the structural and binding properties of RBDs ( Jiang et al, 2005 ; Du et al, 2014 ; Shang et al, 2020b ; Tai et al, 2020 ). Additional sites for intervention against viral infection include the spike S2 stalk that contains HR1 and HR2 hydrophobic regions; stable six-helix-bundle (6-HB) structures that fuse the virus with the host cell membrane ( Figure 2 ) ( Bosch et al, 2003 ; Bosch et al, 2004 ; Aydin et al, 2014 ; Wang et al, 2019 ). These mechanisms might represent sites for intervention against viral replication because targeting these hydrophobic regions has been shown to restrict infection of HIV-1 ( Kong et al, 2016 ; Yuan et al, 2019 ), SARS-CoV-2, and other coronaviruses ( Bosch et al, 2004 ; Xia et al, 2019a ; Xia et al, 2019b ; Wang et al, 2019 ; Xia et al, 2020 ).…”

Section: Inhibition Of Coronaviruses At the Entry Levelmentioning

confidence: 99%

Role of Endolysosomes in Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Coronavirus Disease 2019 Pathogenesis: Implications for Potential Treatments

2020

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an enveloped, single-stranded RNA virus. Humans infected with SARS-CoV-2 develop a disease known as coronavirus disease 2019 (COVID-19) with symptoms and consequences including acute respiratory distress syndrome (ARDS), cardiovascular disorders, and death. SARS-CoV-2 appears to infect cells by first binding viral spike proteins with host protein angiotensin-converting enzyme 2 (ACE2) receptors; the virus is endocytosed following priming by transmembrane protease serine 2 (TMPRSS2). The process of virus entry into endosomes and its release from endolysosomes are key features of enveloped viruses. Thus, it is important to focus attention on the role of endolysosomes in SARS-CoV-2 infection. Indeed, coronaviruses are now known to hijack endocytic machinery to enter cells such that they can deliver their genome at replication sites without initiating host detection and immunological responses. Hence, endolysosomes might be good targets for developing therapeutic strategies against coronaviruses. Here, we focus attention on the involvement of endolysosomes in SARS-CoV-2 infection and COVID-19 pathogenesis. Further, we explore endolysosome-based therapeutic strategies to restrict SARS-CoV-2 infection and COVID-19 pathogenesis.

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Section: Inhibition Of Coronaviruses At the Entry Levelmentioning

confidence: 99%

Role of Endolysosomes in Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Coronavirus Disease 2019 Pathogenesis: Implications for Potential Treatments

2020

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“…Peptide-conjugates utilize peptides such as those derived from natural receptors [219] or bicyclic peptides have shown better tumor penetration [18]. Peptideantibody fusions have been recently generated against Middle East Respiratory Syndrome Coronavirus [220].…”

Section: Small-scaffold Multispecific Modalitiesmentioning

confidence: 99%

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

Zhong

D’Antona

2021

Antibodies

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Recombinant protein-based biotherapeutics drugs have transformed clinical pipelines of the biopharmaceutical industry since the launch of recombinant insulin nearly four decades ago. These biologic drugs are structurally more complex than small molecules, and yet share a similar principle for rational drug discovery and development: That is to start with a pre-defined target and follow with the functional modulation with a therapeutic agent. Despite these tremendous successes, this “one target one drug” paradigm has been challenged by complex disease mechanisms that involve multiple pathways and demand new therapeutic routes. A rapidly evolving wave of multispecific biotherapeutics is coming into focus. These new therapeutic drugs are able to engage two or more protein targets via distinct binding interfaces with or without the chemical conjugation to large or small molecules. They possess the potential to not only address disease intricacy but also exploit new therapeutic mechanisms and assess undruggable targets for conventional monospecific biologics. This review focuses on the recent advances in molecular design and applications of major classes of multispecific biotherapeutics drugs, which include immune cells engagers, antibody-drug conjugates, multispecific tetherbodies, biologic matchmakers, and small-scaffold multispecific modalities. Challenges posed by the multispecific biotherapeutics drugs and their future outlooks are also discussed.

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“…Chimeric antibody-enzyme proteins help to increase tumor specificity, increase therapeutic potency, and reduce side effects compared to conventional cancer therapies (Andrady et al, 2011). Recently, application of chimeric proteins antibodyantiviral peptide for the treatment of MERS virus was reported (Wang et al, 2019). Thus, the use of a chimeric 8P9R-antispike peptide could efficiently inhibit the SARS-CoV-2 from entering the cells and replicating while providing more specificity for 8P9R to bind SARS-CoV-2.…”

Section: Chimeric 8p9r For Early Neutralization Of Sars-cov-2mentioning

confidence: 99%

Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2

Nazerian

Vakili

Ebrahimi

et al. 2021

Front. Cell Dev. Biol.

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Currently, the COVID-19 pandemic is an international challenge, largely due to lack of effective therapies. Pharmacotherapy has not yet been able to find a definitive treatment for COVID-19. Since SARS-CoV-2 affects several organs, treatment strategies that target the virus in a wider range are expected to be ultimately more successful. To this end, a two-step treatment strategy has been presented. In the first phase of the disease, when the patient is newly infected with the virus and the cytokine storm has not yet been developed, a chimeric peptide is used to inhibit virus entry into the host cell cytosol (by inhibiting endosomal pH acidification) and viral replication. After the virus entry and decrease of angiotensin converting enzyme 2 (ACE2) level, some people are unable to properly compensate for the ACE2 pathway and progress toward the cytokine storm. In the beginning of the cytokine storm, sACE2 protein is very effective in regulating the immune system toward the anti-inflammatory pathway, including M2 macrophages. Hence, the genes of 8P9R chimeric peptide and sACE2 would be inserted in an episomal vector with a separate promoter for each gene: the chimeric peptide gene promoter is a CMV promoter, while the sACE2 gene promoter is a NF-κB-sensitive promoter. The NF-κB-sensitive promoter induces the expression of sACE2 gene soon after elevation of NF-κB which is the main transcription factor of inflammatory genes. Thus, as the expression of inflammatory cytokines increases, the expression of sACE2 increases simultaneously. In this condition, sACE2 can prevent the cytokine storm by inhibiting the pro-inflammatory pathways. To deliver the designed vector to the target cells, mesenchymal stem cell-derived (MSC-derived) exosome-liposome hybrids are used. Herein, the strategy can be considered as a personalized clinical therapy for COVID-19, that can prevent morbidity and mortality in the future.

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Engineering a Novel Antibody-Peptide Bispecific Fusion Protein Against MERS-CoV

Cited by 11 publications

References 55 publications

Role of Endolysosomes in Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Coronavirus Disease 2019 Pathogenesis: Implications for Potential Treatments

Role of Endolysosomes in Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Coronavirus Disease 2019 Pathogenesis: Implications for Potential Treatments

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2

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