scholarly journals COVID-19 Coronavirus spike protein analysis for synthetic vaccines, a peptidomimetic antagonist, and therapeutic drugs, and analysis of a proposed achilles’ heel conserved region to minimize probability of escape mutations and drug resistance

2020 ◽  
Vol 121 ◽  
pp. 103749 ◽  
Author(s):  
B. Robson
Keyword(s):  
Drug Resistance ◽  
Protein Analysis ◽  
Spike Protein ◽  
Synthetic Vaccines ◽  
Therapeutic Drugs ◽  
Conserved Region

scholarly journals SARS-CoV-2 Omicron variant escapes neutralization by vaccinated and convalescent sera and therapeutic monoclonal antibodies

2021 ◽  
Author(s):  
Nariko Ikemura ◽  
Atsushi Hoshino ◽  
Yusuke Higuchi ◽  
Shunta Taminishi ◽  
Tohru Inaba ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Viral Escape ◽  
Spike Protein ◽  
The Novel ◽  
Neutralization Titer ◽  
Neutralization Activity ◽  
Therapeutic Drugs ◽  
Conserved Region ◽  
Therapeutic Monoclonal Antibodies

The novel SARS-CoV-2 variant, Omicron (B.1.1.529) contains about 30 mutations in the spike protein and the numerous mutations raise the concern of escape from vaccine, convalescent sera and therapeutic drugs. Here we analyze the alteration of their neutralizing titer with Omicron pseudovirus. Sera of 3 months after double BNT162b2 vaccination exhibite ~27-fold lower neutralization titers against Omicron than D614G mutation. Neutralization titer is also reduced in convalescent sera from Alpha and Delta patients. However, some Delta patients have relatively preserved neutralization activity up to the level of 3-month double BNT162b2 vaccination. Omicron escapes from the cocktail of imdevimab and casirivimab, whereas sotrovimab that targets the conserved region to prevent viral escape is effective to Omicron similarly to the original SARS-CoV-2. The ACE2 decoy is another modality that neutralize the virus independently of mutational escape and Omicron is also sensitive to the engineered ACE2.

TMPRSS2 activates hemagglutinin-esterase glycoprotein of influenza C virus

2021 ◽  
Author(s):  
Ko Sato ◽  
Hideki Hayashi ◽  
Yoshitaka Shimotai ◽  
Mutsuo Yamaya ◽  
Seiji Hongo ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Serine Proteases ◽  
Influenza A ◽  
Respiratory Illness ◽  
Amino Acid Sequences ◽  
Spike Protein ◽  
Human Airway ◽  
Therapeutic Drugs ◽  
Influenza C Virus ◽  
Step Growth

Influenza C virus (ICV) has only one kind of spike protein, the hemagglutinin-esterase (HE) glycoprotein. HE functions similarly to hemagglutinin (HA) and neuraminidase of the influenza A and B viruses (IAV/IBV). It has a monobasic site, which is cleaved by some host enzyme(s). The cleavage is essential to activating the virus, but the enzyme(s) in the respiratory tract has not been identified. This study investigated whether the host serine proteases, transmembrane protease serine S1, members 2 (TMPRSS2), and human airway trypsin-like protease (HAT), which reportedly cleave HA of IAV/IBV, are involved in HE cleavage. We established TMPRSS2- and HAT-expressing MDCK (MDCK-TMPRSS2, MDCK-HAT) cells. ICV showed multicycle replication with HE cleavage without trypsin in MDCK-TMPRSS2 cells as well as IAV did. The HE cleavage and multicycle replication did not appear in MDCK-HAT cells infected with ICV without trypsin, while HA cleavage and multi-step growth of IAV appeared in the cells. Amino acid sequences of the HE cleavage site in 352 ICV strains were completely preserved. Camostat and nafamostat suppressed the growth of ICV and IAV in human nasal surface epithelial (HNE) cells. Therefore, this study revealed that, at least, TMPRSS2 is involved in HE cleavage and suggested that nafamostat could be a candidate for therapeutic drugs of ICV infection. Importance Influenza C virus (ICV) is a pathogen that causes acute respiratory illness, mostly in children, but there are no anti-ICV drugs. ICV has only one kind of spike protein, the hemagglutinin-esterase (HE) glycoprotein on the virion surface, that possesses receptor binding, receptor destroying, and membrane fusion activities. The HE cleavage is essential for the virus to be activated, but the enzyme(s) in the respiratory tract has not been identified. This study revealed that transmembrane protease serine S1, members 2 (TMPRSS2), and not human airway trypsin-like protease (HAT), is involved in HE cleavage. This is a novel study on the host enzymes involved in HE cleavage, and the result suggests that the host enzymes, such as TMPRSS2, may be a target for therapeutic drugs of the ICV infection.

scholarly journals Engineered ACE2 counteracts vaccine-evading SARS-CoV-2 Omicron variant

2021 ◽  
Author(s):  
Nariko Ikemura ◽  
Shunta Taminishi ◽  
Tohru Inaba ◽  
Takao Arimori ◽  
Daisuke Motooka ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Mutational Analysis ◽  
High Sensitivity ◽  
Binding Domain ◽  
Spike Protein ◽  
The Novel ◽  
Receptor Binding Domain ◽  
Therapeutic Drugs ◽  
Viral Mutation ◽  
Therapeutic Value

The novel SARS-CoV-2 variant, Omicron (B.1.1.529) contains an unusually high number of mutations (>30) in the spike protein, raising concerns of escape from vaccines, convalescent sera and therapeutic drugs. Here we analyze the alteration of neutralizing titer with Omicron pseudovirus. Sera of 3 months after double BNT162b2 vaccination exhibit approximately 18-fold lower neutralization titers against Omicron. Convalescent sera from Alpha and Delta patients allow similar levels of breakthrough by Omicron. However, some Delta patients have relatively preserved neutralization efficacy, comparable to 3-month double BNT162b2 vaccination. Domain-wise analysis using chimeric spike revealed that this efficient evasion was, at least in part, caused by multiple mutations in the N-terminal domain. Omicron escapes the therapeutic cocktail of imdevimab and casirivimab, whereas sotrovimab, which targets a conserved region to avoid viral mutation, remains effective against Omicron. The ACE2 decoy is another virus-neutralizing drug modality that is free, at least in theory, from mutational escape. Deep mutational analysis demonstrated that, indeed, the engineered ACE2 overcomes every single-residue mutation in the receptor-binding domain, similar to immunized sera. Like previous SARS-CoV-2 variants, Omicron and some other sarbecoviruses showed high sensitivity against engineered ACE2, confirming the therapeutic value against diverse variants, including those that are yet to emerge.

scholarly journals Oral and Intranasal Immunization with Recombinant Food-Grade Lactococcus Lactis Expressing High Conserved Region of SARS-CoV-2 Spike Protein Triggers Immunity Responses in Mice

2021 ◽  
Author(s):  
Valentina Yurina ◽  
Oktavia Rahayu Adianingsih ◽  
Nashi Widodo
Keyword(s):  
Viral Infections ◽  
Spike Protein ◽  
Nasal Administration ◽  
Oral Vaccination ◽  
Gene Encoding ◽  
Effective Prevention ◽  
Less Invasive ◽  
Humoral Immune ◽  
Long Time ◽  
Conserved Region

Abstract Background: The COVID-19 pandemic began at the end of 2019 in Wuhan, China, and has spread throughout the world until mid-2021. Thus far, no specific therapy has been found for the coronavirus family. Vaccination still becomes the most effective prevention of pathogenic infections, including viral infections. However, little data show that this vaccination can protect against SARS-CoV-2 virus for a long time. Thus, revaccination needs to be regularly carried out to prevent the occurrence of COVID-19. Vaccination by injection is invasive, and it becomes one of the reasons people refuse to get revaccinated. Therefore, we developed a less invasive vaccine based on oral or nasal administration. The gene encoding the high conserved region (HCR) spike protein was inserted into pNZ8149 and expressed in L. lactis NZ3900. Results: The results of nasal and oral administration in experimental animals showed that L. lactis carrying the HCR gene could induce a humoral immune response, as indicated by an increasing IgG and IgA against SARS-CoV-2 (IgG/IgA-SARS-CoV-2) levels and the lymph cell population after nasal and oral vaccination in mice (p<0.05). Conclusion: This study shows promising results that can be developed into a less invasive alternative to nasal and oral vaccination.

scholarly journals Analysis of Cuorum Sensing-Dependent Virulence Factors and Drug Resistance in Pseudomonas Aeruginosa Strains

2021 ◽  
pp. 46-51
Author(s):  
José José de Jesús Alba-Romero ◽  
Pablo Ruiz-Flores ◽  
Graciela Castro-Escarpulli ◽  
Sandra Isabel Hernández-González ◽  
Aurora Martínez-Romero ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Drug Resistance ◽  
Antibiotic Resistance ◽  
Risk Factor ◽  
Virulence Factors ◽  
Virulence Factor ◽  
Protein Analysis ◽  
Hospitalized Patients ◽  
Clinical Samples ◽  
Beta Lactamase

The objective was to analyze the virulence factors dependent on Cuorum Sensing and drug resistance in strains of Pseudomonas aeruginosa. Virulence factors such as pyocyanin, beta-lactamase, biofilm, and antibiotic resistance were determined in 95 strains of P. aeruginosa isolated from hospitalized patients. Genus and species were identified by protein analysis by MALDI-TOF. 100% of the strains were resistant to at least one drug and the highest proportion was 32 strains resistant to 4 drugs and 5 resistant PAM strains. In the analysis of virulence factors, 98.8% produce at least one virulence factor and 48.9% are beta-lactamase producers. Therefore, it is concluded that P. aeruginosa strains isolated from clinical samples constitute a risk factor for hospitalized patients.

scholarly journals Targeting Nrf2 may reverse the drug resistance in ovarian cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Danjie Li ◽  
Xiaoling Hong ◽  
Feijie Zhao ◽  
Xinxin Ci ◽  
Songling Zhang
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Acquired Resistance ◽  
Chemotherapy Resistance ◽  
Ovarian Cancer Cells ◽  
Regulation Of Transcription ◽  
Related Factor ◽  
Main Body ◽  
Chemotherapy Drugs ◽  
Therapeutic Drugs

Abstract Background Acquired resistance to therapeutic drugs has become an important issue in treating ovarian cancer. Studies have shown that the prevalent chemotherapy resistance (cisplatin, paclitaxel etc.) for ovarian cancer occurs partly because of decreased production of reactive oxygen species within the mitochondria of ovarian cancer cells. Main Body Nuclear erythroid-related factor-2 (Nrf2) mainly controls the regulation of transcription of genes through the Keap1-Nrf2-ARE signaling pathway and protects cells by fighting oxidative stress and defending against harmful substances. This protective effect is reflected in the promotion of tumor cell growth and their resistance to chemotherapy drugs. Therefore, inhibition of the Nrf2 pathway may reverse drug resistance. In this review, we describe the functions of Nrf2 in drug resistance based on Nrf2-associated signaling pathways determined in previous studies. Conclusions Further studies on the relevant mechanisms of Nrf2 may help improve the outcomes of ovarian cancer therapy.

scholarly journals The Promise of Mutation Resistant Drugs for SARS-CoV-2 that Interdict in the Folding of the Spike Protein Receptor Binding Domain

COVID ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 288-302
Author(s):  
Fernando Bergasa-Caceres ◽  
Herschel A. Rabitz
Keyword(s):  
Receptor Binding ◽  
Drug Target ◽  
Binding Domain ◽  
Spike Protein ◽  
Folding Pathway ◽  
Receptor Binding Domain ◽  
Double Mutation ◽  
Therapeutic Drugs ◽  
Protein Receptor ◽  
Collapse Model

In recent work, we proposed that effective therapeutic drugs aimed at treating the SARS-CoV-2 infection could be developed based on interdicting in the early steps of the folding pathway of key viral proteins, including the receptor binding domain (RBD) of the spike protein. In order to provide for a drug target on the protein, the earliest contact-formation event along the dominant folding pathway of the RBD spike protein was predicted employing the Sequential Collapse Model (SCM). The segments involved in the predicted earliest contact were suggested to provide optimal folding interdiction target regions (FITRs) for potential therapeutic drugs, with a focus on folding interdicting peptides (FIPs). In this paper, we extend our analysis to include 13 known single mutations of the RBD spike protein as well as the triple mutation B1.351 and the recent double mutation B1.617.2. The results show that the location of the FITR does not change in any of the 15 studied mutations, providing for a mutation-resistant drug design strategy for the RBD-spike protein.

scholarly journals Generation of Spike-Extracellular Vesicles (S-EVs) as a Tool to Mimic SARS-CoV-2 Interaction with Host Cells

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 146
Author(s):  
Roberta Verta ◽  
Cristina Grange ◽  
Renata Skovronova ◽  
Adele Tanzi ◽  
Licia Peruzzi ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Size Structure ◽  
Super Resolution ◽  
Host Cells ◽  
Spike Protein ◽  
Vector Coding ◽  
Therapeutic Drugs ◽  
Pre Treatment ◽  
Host Virus Interactions ◽  
Virus Interactions

Extracellular vesicles (EVs) and viruses share common features: size, structure, biogenesis and uptake. In order to generate EVs expressing the SARS-CoV-2 spike protein on their surface (S-EVs), we collected EVs from SARS-CoV-2 spike expressing human embryonic kidney (HEK-293T) cells by stable transfection with a vector coding for the S1 and S2 subunits. S-EVs were characterized using nanoparticle tracking analysis, ExoView and super-resolution microscopy. We obtained a population of EVs of 50 to 200 nm in size. Spike expressing EVs represented around 40% of the total EV population and co-expressed spike protein with tetraspanins on the surfaces of EVs. We subsequently used ACE2-positive endothelial and bronchial epithelial cells for assessing the internalization of labeled S-EVs using a cytofluorimetric analysis. Internalization of S-EVs was higher than that of control EVs from non-transfected cells. Moreover, S-EV uptake was significantly decreased by anti-ACE2 antibody pre-treatment. Furthermore, colchicine, a drug currently used in clinical trials, significantly reduced S-EV entry into the cells. S-EVs represent a simple, safe, and scalable model to study host-virus interactions and the mechanisms of novel therapeutic drugs.

scholarly journals Distant residues modulate conformational opening in SARS-CoV-2 spike protein

2021 ◽  
Vol 118 (43) ◽  
pp. e2100943118
Author(s):  
Dhiman Ray ◽  
Ly Le ◽  
Ioan Andricioaei
Keyword(s):  
Drug Resistance ◽  
Good Reason ◽  
Experimental Studies ◽  
Graph Connectivity ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Long Distance ◽  
Allosteric Sites ◽  
Time Lagged

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) involves the attachment of the receptor-binding domain (RBD) of its spike proteins to the ACE2 receptors on the peripheral membrane of host cells. Binding is initiated by a down-to-up conformational change in the spike protein, the change that presents the RBD to the receptor. To date, computational and experimental studies that search for therapeutics have concentrated, for good reason, on the RBD. However, the RBD region is highly prone to mutations, and is therefore a hotspot for drug resistance. In contrast, we here focus on the correlations between the RBD and residues distant to it in the spike protein. This allows for a deeper understanding of the underlying molecular recognition events and prediction of the highest-effect key mutations in distant, allosteric sites, with implications for therapeutics. Also, these sites can appear in emerging mutants with possibly higher transmissibility and virulence, and preidentifying them can give clues for designing pan-coronavirus vaccines against future outbreaks. Our model, based on time-lagged independent component analysis (tICA) and protein graph connectivity network, is able to identify multiple residues that exhibit long-distance coupling with the RBD opening. Residues involved in the most ubiquitous D614G mutation and the A570D mutation of the highly contagious UK SARS-CoV-2 variant are predicted ab initio from our model. Conversely, broad-spectrum therapeutics like drugs and monoclonal antibodies can target these key distant-but-conserved regions of the spike protein.

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