Design of peptide-based epitope vaccine and further binding site scrutiny led to groundswell in drug discovery against Lassa virus (original) (raw)
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International Journal of Peptide Research and Therapeutics
Lassa virus (LASV) is responsible for a type of acute viral haemorrhagic fever referred to as Lassa fever. Lack of adequate treatment and preventive measures against LASV resulted in a high mortality rate in its endemic regions. In this study, a multi-epitope vaccine was designed using immunoinformatics as a prophylactic agent against the virus. Following a rigorous assessment, the vaccine was built using T-cell (N CTL = 8 and N HTL = 6) and B-cell (N LBL = 4) epitopes from each LASV-derived protein in addition with suitable linkers and adjuvant. The physicochemistry, immunogenic potency and safeness of the designed vaccine (~ 68 kDa) were assessed. In addition, chosen CTL and HTL epitopes of our vaccine showed 97.37% worldwide population coverage. Besides, disulphide engineering also improved the stability of the chimeric vaccine. Molecular docking of our vaccine protein with toll-like receptor 2 (TLR2) showed binding efficiency followed by dynamics simulation for stable interaction. Furthermore, higher levels of cell-mediated immunity and rapid antigen clearance were suggested by immune simulation and repeated-exposure simulation, respectively. Finally, the optimized codons were used in in silico cloning to ensure higher expression within E. coli K12 bacterium. With further assessment both in vitro and in vivo, we believe that our proposed peptide-vaccine would be potential immunogen against Lassa fever.
Lassa virus (LASV) is responsible for a type of acute viral haemorrhagic fever referred to as Lassa fever. Lack of adequate treatment and preventive measures against LASV resulted in a high mortality rate in its endemic regions. In this study, a multi-epitope vaccine was designed using immunoinformatics as a prophylactic agent against the virus. Following a rigorous assessment, the vaccine was built using T-cell (NCTL=8 and NHTL=6) and B-cell (NLBL=4) epitopes from each LASV-derived protein with suitable linkers and adjuvant. The physicochemistry, immunogenic potency and safeness of the designed vaccine (~68 kDa) were assessed. In addition, chosen CTL and HTL epitopes of our vaccine showed 97.37% worldwide population coverage. Besides, disulphide engineering also improved the stability of the chimeric vaccine. Molecular docking of our vaccine protein with toll-like receptor (TLR2) showed binding efficiency followed by dynamic simulation for stable interaction. Furthermore, higher le...
Computer aided epitope design as a peptide vaccine component against Lassa virus
Bioinformation, 2017
Lassa virus (LASV) is an arena virus causing hemorrhagic fever and it is endemic in several regions of West Africa. The disease-causing virus records high mortality rate in endemic regions due to lack of appropriate treatment and prevention strategies. Therefore, it is ofinterest to design and develop viable vaccine components against the virus. We used the Lassa virus envelope glyco-proteins as a vaccine target to identify linear peptides as potential epitopes with immunogenic properties by computer aided epitope predictiontools. We report a T-cell epitope ÔLLGTFTWTLÕ and a B-cell epitope ÔAELKCFGNTAVAKCNEÕ with predicted potentialimmunogenicity for further in vivo and in vitro consideration
Clinical and Experimental Vaccine Research
Lassa fever is a zoonotic acute viral hemorrhagic disease caused by Lassa virus (LASV). There is currently no licensed vaccine for the prevention of the disease. This study is aimed at discovering immunodominant epitopes from the envelope glycoprotein of the Lassa mammarenavirus and designing of a multi-epitope vaccine candidate (VC). Materials and Methods: The amino acid sequences of the envelope glycoprotein of 26 strains of LASV from five countries were selected. After evaluation for antigenicity, immunogenicity, allergenicity, and toxicity, immunodominant CD8, CD4, and linear B lymphocytes were also selected. The selected epitopes were modelled and a molecular docking with the appropriate major histocompatibility complex (MHC) proteins was performed. Using an adjuvant and linkers, a multi-epitope VC was designed. The VC was evaluated for its physicochemical and immunological properties and structurally refined, validated, and mutated (disulphide engineering). The complex formed by the VC and the toll-like receptor-4 receptor was subjected to molecular dynamic simulation (MDS) followed by in silico cloning in a plasmid vector. Results: A VC with 203 sequences, 22.13 kDa weight, isoelectric point of 9.85 (basic), instability index value of 27.62, aliphatic index of 68.87, and GRAVY value of-0.455 (hydrophilic) emerged. The VC is predicted to be non-allergenic with antigenicity, MHC I immunogenicity, and solubility upon overexpression values of 0.81, 2.04, and 0.86 respectively. The VC also has an estimated half-life greater than 10 hours in Escherichia coli and showed stability in all the parameters of MDS. Conclusion: The VC shows good promise in the prevention of Lassa fever but further tests are required to validate its safety and efficacy.
Identification of Protective Lassa Virus Epitopes That Are Restricted by HLA-A2
Journal of Virology, 2006
indicating that cellular immunity plays a primary role in viral clearance. To date, the role of LASV-specific CD8 ؉ T cells has not been evaluated in humans. To facilitate such studies, we utilized a predictive algorithm to identify candidate HLA-A2 supertype epitopes from the LASV nucleoprotein and glycoprotein precursor (GPC) genes. We identified three peptides (GPC 42-50 , GLVGLVTFL; GPC 60-68 , SLYKGVYEL; and GPC 441-449 , YLISIFLHL) that displayed high-affinity binding (<98 nM) to HLA-A*0201, induced CD8 ؉ T-cell responses of high functional avidity in HLA-A*0201 transgenic mice, and were naturally processed from native LASV GPC in human HLA-A*0201-positive target cells. HLA-A*0201 mice immunized with either GPC 42-50 or GPC 60-68 were protected against challenge with a recombinant vaccinia virus that expressed LASV GPC. The epitopes identified in this study represent potential diagnostic reagents and candidates for inclusion in epitope-based vaccine constructs. Our approach is applicable to any pathogen with existing sequence data, does not require manipulation of the actual pathogen or access to immune human donors, and should therefore be generally applicable to category A through C agents and other emerging pathogens.
Virology Journal, 2010
Background Lassa fever is a neglected tropical disease with significant impact on the health care system, society, and economy of Western and Central African nations where it is endemic. Treatment of acute Lassa fever infections has successfully utilized intravenous administration of ribavirin, a nucleotide analogue drug, but this is not an approved use; efficacy of oral administration has not been demonstrated. To date, several potential new vaccine platforms have been explored, but none have progressed toward clinical trials and commercialization. Therefore, the development of a robust vaccine platform that could be generated in sufficient quantities and at a low cost per dose could herald a subcontinent-wide vaccination program. This would move Lassa endemic areas toward the control and reduction of major outbreaks and endemic infections. To this end, we have employed efficient mammalian expression systems to generate a Lassa virus (LASV)-like particle (VLP)-based modular vaccine...
Virtual screening for potential inhibitors of Lassa fever nucleoprotein
Communication in Physical Sciences 2020, 5(3): 391-402, 2020
The devastating impact of viral haemorrhagic fevers has deeply been felt in South America and Africa. This fever is caused by the arenaviruses Lassa and has posed a matchless fight. Meanwhile, no effective drug or vaccine has been reported. Here we used virtual screening and molecular docking approach to identify a series of novel inhibitors (ZINC64450313 (-10.7 kcal/mol), ZINC00658482 (-10.5 kcal/mol), ZINC40789449 (-10.5 kcal/mol), ZINC14551223 (10.0 kcal/mol) and ZINC73892903 (10.0 kcal/mol)) that can exhibit significant binding affinity to Lassa fever nucleoprotein (PDB ID: 3mx5) than ribavirin (-6.7 kcal/mol). Swiss ADME web tools were used to assess the pharmacokinetics and drug-likeness characteristics of the lead molecule (ZINC64450313). This assay showed that ZINC64450313 obeyed Lipinski, Egan, Verber and Muegge rules. However, pharmacokinetics predictions indicated that CYP1A2, CYP2C9, CYP2D6 and CYP2C19 isoenzyme were not inhibited by ZINC64450313. Toxicity assay of ZINC64450313 was acquired with an average similarity index of 33.25% and prediction accuracy of 23% on the ProTox-II webserver. The lead molecule has an LD50 value of 10 mg/kg and belongs to toxicity class 2. The frontier molecular orbital's analysis revealed that ZINC64450313 is more reactive than ribavirin due to the possesion of better quantum chemical indices such as its the global hardness. Hence, an in vitro and in vivo assay of these molecules may proffer a pathway to finding effective inhibitors with the potential to truncate functional proteins responsible for the viral life cycle of arenaviruses Lassa.
Journal of Biomolecular Structure and Dynamics, 2020
Background: Chikungunya virus (CHIKV) instigating Chikungunya fever is a global infective menace resulting in high fever, weakened joint-muscle pain, and brain inflammation. Inaccessibility and unavailability of effective drugs have led us to an uncertain arena when it comes to providing proper medical treatment to the affected people. Method: In this study, authentic encroachment has been made concerning the peptide-based epitope vaccine designing against CHIKV. A Proteome-wide search was performed to locate a conserved portion among the accessible viral outer membrane proteins which showcase a remarkable immune response using specific immunoinformatics and docking simulation tools. Results: Primarily, the most probable immunogenic envelope glycoproteins E1 and E2 were identified from the UniProt database depending on their antigenicity scores. Subsequently, we selected two distinctive sequences "SEDVYANTQLVLQRP" and "IMLLYPDHPTLLSYR" in both E1 and E2 glycoproteins respectively. These two sequences identified as the most potent T and B cell epitope-based peptides as they interacted with 6 and 7 HLA-I and 5 HLA-II molecules with an extremely low IC50 score that was verified by molecular docking. Moreover, the sequences possess no allergenicity and are certainly located outside the transmembrane region. In addition, the sequences exhibited 88.46% and 100.00% Conservancy, covering high population coverage of 89.49% to 94.74% and 60.51% to 88.87% respectively in endemic countries. Conclusion: The identified peptide SEDVYANTQLVLQRP and IMLLYPDHPTLLSYR can be utilized next for the development of peptide-based epitope vaccine contrary to CHIKV, So further documentations and experimentations like Antigen testing, Antigen production, Clinical trials are needed to prove the validity of it.
Lassa virus glycoproteins: antigenic and immunogenic properties of synthetic peptides to GP1
Archives of Virology, 1990
Synthetic peptides corresponding to predicted Lassa virus GP1 glycoprotein B-epitopes were used to study the antigenicity and immunogenicity of the protein. ELISA results showed that guinea pig polyclonal anti-Lassa virus serum bound effectively to peptides corresponding to amino acid residues 119–133 and 164–176 of the GP1 protein. Essentially it did not react to a peptide corresponding to GP1 amino acid residues 234–256. Sera obtained against peptides representing amino acid residues 119–133 and 164–176 reacted with inactivated purified Lassa virus.