scholarly journals Immunoinformatic approach to design a multiepitope vaccine targeting non-mutational hotspot regions of structural and non-structural proteins of the SARS CoV2

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11126
Author(s):  
Vandana Solanki ◽  
Monalisa Tiwari ◽  
Vishvanath Tiwari
Keyword(s):  
Immune Response ◽  
Binding Affinity ◽  
Antigen Processing ◽  
Clonal Selection ◽  
3D Structure ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Structural Proteins ◽  
Morbidity Rate ◽  
Subtractive Proteomics

Background The rapid Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV2) outbreak caused severe pandemic infection worldwide. The high mortality and morbidity rate of SARS CoV2 is due to the unavailability of vaccination and mutation in this virus. The present article aims to design a potential vaccine construct VTC3 targeting the non-mutational region of structural and non-structural proteins of SARS CoV2. Methods In this study, vaccines were designed using subtractive proteomics and reverse vaccinology. To target the virus adhesion and evasion, 10 different structural and non-structural proteins have been selected. Shortlisted proteins have been screened for B cell, T cell and IFN gamma interacting epitopes. 3D structure of vaccine construct was modeled and evaluated for its physicochemical properties, immunogenicity, allergenicity, toxicity and antigenicity. The finalized construct was implemented for docking and molecular dynamics simulation (MDS) with different toll-like receptors (TLRs) and human leukocyte antigen (HLA). The binding energy and dissociation construct of the vaccine with HLA and TLR was also calculated. Mutational sensitivity profiling of the designed vaccine was performed, and mutations were reconfirmed from the experimental database. Antibody production, clonal selection, antigen processing, immune response and memory generation in host cells after injection of the vaccine was also monitored using immune simulation. Results Subtractive proteomics identified seven (structural and non-structural) proteins of this virus that have a role in cell adhesion and infection. The different epitopes were predicted, and only extracellular epitopes were selected that do not have similarity and cross-reactivity with the host cell. Finalized epitopes of all proteins with minimum allergenicity and toxicity were joined using linkers to designed different vaccine constructs. Docking different constructs with different TLRs and HLA demonstrated a stable and reliable binding affinity of VTC3 with the TLRs and HLAs. MDS analysis further confirms the interaction of VTC3 with HLA and TLR1/2 complex. The VTC3 has a favorable binding affinity and dissociation constant with HLA and TLR. The VTC3 does not have similarities with the human microbiome, and most of the interacting residues of VTC3 do not have mutations. The immune simulation result showed that VTC3 induces a strong immune response. The present study designs a multiepitope vaccine targeting the non-mutational region of structural and non-structural proteins of the SARS CoV2 using an immunoinformatic approach, which needs to be experimentally validated.

scholarly journals Development of a Conserved Chimeric Vaccine for Induction of Strong Immune Response against Staphylococcus aureus Using Immunoinformatics Approaches

Vaccines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1038
Author(s):  
Rahul Chatterjee ◽  
Panchanan Sahoo ◽  
Soumya Ranjan Mahapatra ◽  
Jyotirmayee Dey ◽  
Mrinmoy Ghosh ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Response ◽  
Multidrug Resistant ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Population Coverage ◽  
Strong Immune Response ◽  
Chimeric Vaccine

Staphylococcus aureus is one of the most notorious Gram-positive bacteria with a very high mortality rate. The WHO has listed S. aureus as one of the ESKAPE pathogens requiring urgent research and development efforts to fight against it. Yet there is a major layback in the advancement of effective vaccines against this multidrug-resistant pathogen. SdrD and SdrE proteins are attractive immunogen candidates as they are conserved among all the strains and contribute specifically to bacterial adherence to the host cells. Furthermore, these proteins are predicted to be highly antigenic and essential for pathogen survival. Therefore, in this study, using the immunoinformatics approach, a novel vaccine candidate was constructed using highly immunogenic conserved T-cell and B-cell epitopes along with specific linkers, adjuvants, and consequently modeled for docking with human Toll-like receptor 2. Additionally, physicochemical properties, secondary structure, disulphide engineering, and population coverage analysis were also analyzed for the vaccine. The constructed vaccine showed good results of worldwide population coverage and a promising immune response. For evaluation of the stability of the vaccine-TLR-2 docked complex, a molecular dynamics simulation was performed. The constructed vaccine was subjected to in silico immune simulations by C-ImmSim and Immune simulation significantly provided high levels of immunoglobulins, T-helper cells, T-cytotoxic cells, and INF-γ. Lastly, upon cloning, the vaccine protein was reverse transcribed into a DNA sequence and cloned into a pET28a (+) vector to ensure translational potency and microbial expression. The overall results of the study showed that the designed novel chimeric vaccine can simultaneously elicit humoral and cell-mediated immune responses and is a reliable construct for subsequent in vivo and in vitro studies against the pathogen.

scholarly journals COVID-19 : histoire, pathogenèse et réponse immunitaire de l'hôte

2021 ◽  
Vol 8 (1) ◽  
pp. 52-58
Author(s):  
Takieddine Hamadou ◽  
◽  
Imene Hamadou ◽  
Ahmed Menad ◽  
Somia Bouameur ◽  
...  
Keyword(s):  
Immune Response ◽  
Current Knowledge ◽  
Rna Virus ◽  
Multiorgan Failure ◽  
Alveolar Epithelial Cells ◽  
Host Cells ◽  
Disease Spread ◽  
Structural Proteins ◽  
Unknown Etiology ◽  
Presenting Symptoms

By the end of 2019, pneumonia of unknown etiology occurred in Wuhan, China. Local hospitals started receiving patients presenting symptoms like dry cough, fatigue, and breathing difficulties, most of these patients were linked to the Huanan seafood market, Wuhan, China. The pandemic was afterward confirmed to be associated with a novel coronavirus. The virus spread quickly from Wuhan to other provinces of China, then from china to the rest of the world causing thereby one of the most brutal pandemics in the world’s history. SARS-CoV2 has a long incubation period ranging from 3 to 7 days and can go up to 14 days in some cases which makes the infection difficult to be detected early and subsequently the disease spread harder to be controlled. SARS-CoV-2 is a single-stranded RNA virus with 4 main structural proteins, the spike (S) glycoprotein, the small envelope (E) the glycoprotein, the membrane (M) glycoprotein as well as the nucleocapsid (N) protein. Current knowledge about the virus shows that it uses its spike protein to invade host cells, mainly the alveolar epithelial cells. The the lung is the most targeted organ among many other organs like the heart, small intestine, and kidneys that are vulnerable to SARS-CoV-2 infection. The COVID-19 is known to be mild in most cases, but in some cases, it can be severe or even fatal. In the severe cases, acute respiratory distress syndrome was reported, and the the capability of SARS-CoV-2 to infect many organs can lead to multiorgan failure and death. SARS-CoV-2 invasion induces several immune responses that could be efficient for infection clearance in mild cases, while in severe cases, the immune response dysfunctions can even contribute to the disease aggravation. Neither the the pathogenic mechanism by which SARS-CoV-2 infects host cells, nor the host immune response to its infection have been fully understood, hence further studies are needed to give further evidence about these two phenomena. Keywords: COVID-19, SARS-CoV-2, Coronavirus, Structural proteins, Immune response.

scholarly journals Exploring the structural basis to develop efficient multi-epitope vaccines displaying interaction with HLA and TAP and TLR3 molecules to prevent NIPAH infection, a global threat to human health

2021 ◽  
Author(s):  
Sukrit Srivastava ◽  
Ajay Kumar Saxena ◽  
Michael Kolbe
Keyword(s):  
Immune Response ◽  
B Cell ◽  
T Lymphocyte ◽  
Antigen Processing ◽  
Dynamics Simulation ◽  
Structural Basis ◽  
Effective Vaccine ◽  
Mammalian Host ◽  
Ctl Epitopes ◽  
Epitope Vaccines

Nipah virus (NiV) is an emerging zoonotic virus responsible to cause several serious outbreaks in South Asian region with high mortality rate of 40 to 90% since 2001. NiV infection causes lethal encephalitis and respiratory disease with the symptom of endothelial cell-cell fusion. No specific vaccine has yet been reported against NiV infection. Recently, some Multi-Epitope Vaccines (MEV) has been proposed but they involve limited number of epitopes which further limits the potential of vaccine. To address the urgent need for a specific and effective vaccine against NiV infection, in the present study, we have design two multi-epitope vaccines (MEVs) composed of 33 Cytotoxic T lymphocyte (CTL) epitopes and 38 Helper T lymphocyte (HTL) epitopes. Both the MEVs carry potential B cell linear epitope overlapping regions, B cell discontinuous epitopes as well as IFN-γ inducing epitopes. Hence the designed MEVs carry potential to elicit cell-mediated as well as humoral immune response. Selected CTL and HTL epitopes were validated for their stable molecular interactions with HLA class I and II alleles as well as in case of CTL epitopes, with human transporter associated with antigen processing (TAP). Human β-defensin 2 and β-defensin 3 were used as adjuvants to enhance the immune response of both the MEVs. The molecular dynamics simulation study of MEVs-TLR3(ECD) (Toll-Like Receptor 3 Ectodomain) complex indicated stable molecular interaction. Further, the codon optimized cDNA of both the MEVs has shown high expression potential in the mammalian host cell line (Human). Hence for further studies, both the design of CTL and HTL MEVs could be cloned, expressed and tried for in-vivo validations (animal trails) as potential vaccine candidates against NiV infection.

scholarly journals A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients

2020 ◽  
Author(s):  
Dharmendra Kumar Maurya
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Binding Affinity ◽  
Viral Entry ◽  
Virus Disease ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Host Immune System ◽  
Main Protease ◽  
Approved Drugs

<p></p><p>The current outbreak of the corona virus disease 2019 (COVID-19), has affected almost entire world and become pandemic now. Currently, there is neither any FDA approved drugs nor any vaccines available to control it. Very recently in Bangladesh, a group of doctors reported astounding success in treating patients suffering from COVID-19 with two commonly used drugs, Ivermectin and Doxycycline. In the current study we have explored the possible mechanism by which these drugs might have worked for the positive response in the COVID-19 patients. To explore the mechanism we have used molecular docking and molecular dynamics simulation approach. Effectiveness of Ivermectin and doxycycline were evaluated against Main Protease (Mpro), Spike (S) protein, Nucleocapsid (N), RNA-dependent RNA polymerase (RdRp, NSP12), ADP Ribose Phosphatase (NSP3), Endoribonuclease (NSP15) and methyltransferase (NSP10-NSP16 complex) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor. Our study shows that both Ivermectin and doxycycline have significantly bind with SARS-CoV-2 proteins but Ivermectin was better binding than doxycycline. Ivermectin showed a perfect binding site to the Spike-RBD and ACE2 interacting region indicating that it might be interfering in the interaction of spike with ACE2 and preventing the viral entry in to the host cells. Ivermectin also exhibited significant binding affinity with different SARS-CoV-2 structural and non-structural proteins (NSPs) which have diverse functions in virus life cycle. Significant binding of Ivermectin with RdRp indicate its role in the inhibition of the viral replication and ultimately impeding the multiplication of the virus. Ivermectin also possess significant binding affinity with NSP3, NSP10, NSP15 and NSP16 which helps virus in escaping from host immune system. Molecular dynamics simulation study shows that binding of the Ivermectin with Mpro, Spike, NSP3, NSP16 and ACE2 was quiet stable. Thus, our docking and simulation studies reveal that combination of Ivermectin and doxycycline might be executing the effect by inhibition of viral entry and enhance viral load clearance by targeting various viral functional proteins.</p><p></p>

scholarly journals A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients

2020 ◽  
Author(s):  
Dharmendra Kumar Maurya
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Binding Affinity ◽  
Viral Entry ◽  
Virus Disease ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Host Immune System ◽  
Main Protease ◽  
Approved Drugs

<p></p><p>The current outbreak of the corona virus disease 2019 (COVID-19), has affected almost entire world and become pandemic now. Currently, there is neither any FDA approved drugs nor any vaccines available to control it. Very recently in Bangladesh, a group of doctors reported astounding success in treating patients suffering from COVID-19 with two commonly used drugs, Ivermectin and Doxycycline. In the current study we have explored the possible mechanism by which these drugs might have worked for the positive response in the COVID-19 patients. To explore the mechanism we have used molecular docking and molecular dynamics simulation approach. Effectiveness of Ivermectin and doxycycline were evaluated against Main Protease (Mpro), Spike (S) protein, Nucleocapsid (N), RNA-dependent RNA polymerase (RdRp, NSP12), ADP Ribose Phosphatase (NSP3), Endoribonuclease (NSP15) and methyltransferase (NSP10-NSP16 complex) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor. Our study shows that both Ivermectin and doxycycline have significantly bind with SARS-CoV-2 proteins but Ivermectin was better binding than doxycycline. Ivermectin showed a perfect binding site to the Spike-RBD and ACE2 interacting region indicating that it might be interfering in the interaction of spike with ACE2 and preventing the viral entry in to the host cells. Ivermectin also exhibited significant binding affinity with different SARS-CoV-2 structural and non-structural proteins (NSPs) which have diverse functions in virus life cycle. Significant binding of Ivermectin with RdRp indicate its role in the inhibition of the viral replication and ultimately impeding the multiplication of the virus. Ivermectin also possess significant binding affinity with NSP3, NSP10, NSP15 and NSP16 which helps virus in escaping from host immune system. Molecular dynamics simulation study shows that binding of the Ivermectin with Mpro, Spike, NSP3, NSP16 and ACE2 was quiet stable. Thus, our docking and simulation studies reveal that combination of Ivermectin and doxycycline might be executing the effect by inhibition of viral entry and enhance viral load clearance by targeting various viral functional proteins.</p><p></p>

scholarly journals Structure-Based Virtual Screening and Molecular Dynamics of Quercetin and Its Natural Derivatives as Potent Oxidative Stress Modulators in ROS-induced Cancer

2021 ◽  
Vol 3 (2) ◽  
pp. 60
Author(s):  
Abd. Kakhar Umar ◽  
James H. Zothantluanga
Keyword(s):  
Oxidative Stress ◽  
Molecular Dynamics ◽  
Binding Affinity ◽  
3D Structure ◽  
Binding Pocket ◽  
Structure Type ◽  
Dynamics Simulation ◽  
Quercetin Derivatives ◽  
A Value ◽  
The Impact

Quercetin derivatives are known to have significant anticancer activity. The activity is strongly influenced by the type and position of the substituent group. By studying the structural pattern of quercetin and its impact on their binding affinity, the development of quercetin-based drugs can be optimized. The study aimed to determine the impact of 3D structure, type, and position of quercetin moiety on its activity against ROS-modulating enzymes that play a role in the induction and growth of ROS-induced cancer. The 23 natural quercetin derivatives were docked to 7 ROS-modulating enzymes using Autodock Vina to determine their binding affinity and interaction. The interaction stability was further studied through molecular dynamics simulation using the CABS Flex 2.0 server. Determination of crucial amino acid targets of the quercetin group was determined using DockFlin. Finally, the toxicity of each test ligand was determined using the pkCSM server. The highest binding affinity for SOD and NOX was produced by quercetin 3'-glucoside with the binding energy of -10.2 and -12.8 kcal/mol. Quercetin 3,4'-diglucoside had the highest binding affinity for CAT and GR at -11.5 and -10.5 kcal/mol, respectively. Routine produced the highest binding affinity at LOX (-10.9). Quercetin 3-O-xyloside and quercetin 3-O-rhamnoside-7-O-glucoside had the highest binding affinity in XO with a value of -10.4 kcal/mol. The glucose and prenyl groups are beneficial for quercetin in interacting with all ROS-modulating enzymes except XO. In contrast, the methoxy group negatively affects all interactions of quercetin with receptors. The perfect fit between the binding pocket and the 3D structure of the ligand greatly benefits the ligand in accessing more amino acids in the binding pocket. Their interaction stability and toxicity show that quercetin 3'-glucoside, quercetin 3,4'-diglucoside, and rutin are potent oxidative stress modulators in treating ROS-induced cancer.

scholarly journals A Single-Pass Type I Membrane Protein from the Apicomplexan Parasite Cryptosporidium parvum with Nanomolar Binding Affinity to Host Cell Surface

2021 ◽  
Vol 9 (5) ◽  
pp. 1015
Author(s):  
Tianyu Zhang ◽  
Xin Gao ◽  
Dongqiang Wang ◽  
Jixue Zhao ◽  
Nan Zhang ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Cell Surface ◽  
Host Cell ◽  
Binding Affinity ◽  
Cryptosporidium Parvum ◽  
Host Cells ◽  
Watery Diarrhea ◽  
Type I ◽  
Single Pass ◽  
Host Cell Surface

Cryptosporidium parvum is a globally recognized zoonotic parasite of medical and veterinary importance. This parasite mainly infects intestinal epithelial cells and causes mild to severe watery diarrhea that could be deadly in patients with weakened or defect immunity. However, its molecular interactions with hosts and pathogenesis, an important part in adaptation of parasitic lifestyle, remain poorly understood. Here we report the identification and characterization of a C. parvum T-cell immunomodulatory protein homolog (CpTIPH). CpTIPH is a 901-aa single-pass type I membrane protein encoded by cgd5_830 gene that also contains a short Vibrio, Colwellia, Bradyrhizobium and Shewanella (VCBS) repeat and relatively long integrin alpha (ITGA) N-terminus domain. Immunofluorescence assay confirmed the location of CpTIPH on the cell surface of C. parvum sporozoites. In congruence with the presence of VCBS repeat and ITGA domain, CpTIPH displayed high, nanomolar binding affinity to host cell surface (i.e., Kd(App) at 16.2 to 44.7 nM on fixed HCT-8 and CHO-K1 cells, respectively). The involvement of CpTIPH in the parasite invasion is partly supported by experiments showing that an anti-CpTIPH antibody could partially block the invasion of C. parvum sporozoites into host cells. These observations provide a strong basis for further investigation of the roles of CpTIPH in parasite-host cell interactions.

scholarly journals Resveratrol Inhibits Venezuelan Equine Encephalitis Virus Infection by Interfering with the AKT/GSK Pathway

Plants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 346
Author(s):  
Caitlin W. Lehman ◽  
Kylene Kehn-Hall ◽  
Megha Aggarwal ◽  
Nicole R. Bracci ◽  
Han-Chi Pan ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Fluorescent Protein ◽  
Glycogen Synthase ◽  
Venezuelan Equine Encephalitis Virus ◽  
Encephalitis Virus ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Luciferase Reporter ◽  
Venezuelan Equine Encephalitis ◽  
Equine Encephalitis Virus

The host proteins Protein Kinase B (AKT) and glycogen synthase kinase-3 (GSK-3) are associated with multiple neurodegenerative disorders. They are also important for the replication of Venezuelan equine encephalitis virus (VEEV), thereby making the AKT/GSK-3 pathway an attractive target for developing anti-VEEV therapeutics. Resveratrol, a natural phytochemical, has been shown to substantially inhibit the AKT pathway. Therefore, we attempted to explore whether it exerts any antiviral activity against VEEV. In this study, we utilized green fluorescent protein (GFP)- and luciferase-encoding recombinant VEEV to determine the cytotoxicity and antiviral efficacy via luciferase reporter assays, flow cytometry, and immunofluorescent assays. Our results indicate that resveratrol treatment is capable of inhibiting VEEV replication, resulting in increased viability of Vero and U87MG cells as well as reduced virion production and viral RNA contents within host cells for at least 48 h with a single treatment. Furthermore, the suppression of apoptotic signaling adaptors, caspase-3, caspase-7, and annexin V may also be implicated in resveratrol-mediated antiviral activity. We found that decreased phosphorylation of the AKT/GSK-3 pathway, mediated by resveratrol, can be triggered during the early stages of VEEV infection, suggesting that resveratrol disrupts the viral replication cycle and consequently promotes cell survival. Finally, molecular docking and dynamics simulation studies revealed that resveratrol can directly bind to VEEV glycoproteins, which may interfere with virus attachment and entry. In conclusion, our results suggest that resveratrol exerts inhibitory activity against VEEV infection and upon further modification could be a useful compound to study in neuroprotective research and veterinary sciences.

scholarly journals Modeling and Molecular Dynamics of the 3D Structure of the HPV16 E7 Protein and Its Variants

2021 ◽  
Vol 22 (3) ◽  
pp. 1400
Author(s):  
Ciresthel Bello-Rios ◽  
Sarita Montaño ◽  
Olga Lilia Garibay-Cerdenares ◽  
Lilian Esmeralda Araujo-Arcos ◽  
Marco Antonio Leyva-Vázquez ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
3D Structure ◽  
Epidemiological Studies ◽  
Dynamics Simulation ◽  
Structural Refinement ◽  
Oncogenic Potential ◽  
Structural Differences ◽  
Reference Protein ◽  
E6 And E7 ◽  
First Time

The oncogenic potential of high-risk human papillomavirus (HPV) is predicated on the production of the E6 and E7 oncoproteins, which are responsible for disrupting the control of the cell cycle. Epidemiological studies have proposed that the presence of the N29S and H51N variants of the HPV16 E7 protein is significantly associated with cervical cancer. It has been suggested that changes in the amino acid sequence of E7 variants may affect the oncoprotein 3D structure; however, this remains uncertain. An analysis of the structural differences of the HPV16 E7 protein and its variants (N29S and H51N) was performed through homology modeling and structural refinement by molecular dynamics simulation. We propose, for the first time, a 3D structure of the E7 reference protein and two of Its variants (N29S and H51N), and conclude that the mutations induced by the variants in N29S and H51N have a significant influence on the 3D structure of the E7 protein of HPV16, which could be related to the oncogenic capacity of this protein.

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