Characterization of proteome wide antigenic epitopes to design proteins specific and proteome-wide ensemble vaccines against heartland virus using structural vaccinology and immune simulation approaches.

Heartland virus is a single-stranded negative-sense RNA virus that infects humans and causes lethargy, myalgia, headaches, nausea, diarrhea, weight loss, arthralgia, loss of appetite, leukopenia, and easy bruising due thrombocytopenia. The unavailability of antiviral drugs for HRTV infection is a major obstacle to treat this infection, therefore supportive care management is adopted in the case of a severe ailment. In this scientific study, proteins specific and proteome-wide Helper T-cell (HTL), linear B cell, and cytotoxic T-cell (CTL) epitopes mapping joined together with suitable linkers to design multi-epitopes subunit vaccine (MEVC). The constructed four vaccines from nucleocapsid protein, replicase, glycoprotein and finally whole proteome-wide constructs demonstrated stronger antigenic and non-allergenic behavior. Physiochemical properties evaluation also reported easy and efficient expression and downstream analysis of the constructs. Molecular docking of these constructs with toll-like receptor 7 (TLR7) revealed good binding and further validation based on MM/GBSA also demonstrated stronger interaction between the vaccine constructs and TLR7. Moreover, in silico cloning reported CAI value of 0.96 for each construct and excellent GC contents percentage required for experimental analysis. Furthermore, immune simulation-based immune response surveillance revealed that upon the injection of antigen the primary and secondary antibodies were produced between 5 and 15 days, and a more robust neutralization of the antigen by the proteome-wide vaccine construct was observed. This research could pave the way for the development of dynamic and efficient vaccines that contain a unique mix of numerous HRTV derived antigenic peptides to control HRTV infection.

Blocking key mutated hotspot residues in the RBD of the omicron variant (B.1.1.529) with medicinal compounds to disrupt the RBD-hACE2 complex using molecular screening and simulation approaches.

A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world. The omicron variant is reported to be highly contagious with antibody-escaping activity. The emergence of antibody-escaping variants is alarming, and thus the quick discovery of small molecule inhibitors is needed. Hence, the current study uses computational drug screening and molecular dynamics simulation approaches (replicated) to identify novel drugs that can inhibit the binding of the receptor-binding domain (RBD) with hACE2. Screening of the North African, East African and North-East African medicinal compound databases by employing a multi-step screening approach revealed four compounds, namely (-)-pipoxide (C1), 2-(p-hydroxybenzyl) benzofuran-6-ol (C2), 1-(4-hydroxy-3-methoxyphenyl)-2-{4-[(E)-3-hydroxy-1-propenyl]-2-methoxyphenoxy}-1,3-propanediol (C3), and Rhein (C4), with excellent anti-viral properties against the RBD of the omicron variant. Investigation of the dynamics demonstrates stable behavior, good residue flexibility profiles, and structural compactness. Validation of the top hits using computational bioactivity analysis, binding free energy calculations and dissociation constant (K D) analysis also indicated the anti-viral properties of these compounds. In conclusion, this study will help in the design and discovery of novel drug therapeutics, which may be used against the emerging omicron variant of SARS-CoV-2.