Hitting Epstein Barr virus where it hurts: computational methods exploration for siRNA therapy in alleviating Epstein Barr virus-induced multiple sclerosis.

Multiple sclerosis (MS), an intricate neurological disorder, continues to challenge our understanding of the pivotal interplay between the immune system and the central nervous system (CNS). This condition arises from the immune system's misdirected attack on nerve fiber protection, known as myelin sheath, alongside nerve fibers themselves. This enigmatic condition, characterized by demyelination and varied clinical manifestations, prompts exploration into its multifaceted etiology and potential therapeutic avenues. Research has revealed a potential connection between Epstein Barr virus (EBV), specifically Epstein Barr Nuclear Antigen 1 (EBNA-1), and MS. The immune response to EBNA-1 antigen triggers the production of anti-EBNA-1 molecules, including IgG that identify a similar amino acid sequence to EBNA-1 in myelin, inadvertently targeting myelin sheath and contributing to MS progression. Currently, no treatment exists for EBNA-1-induced MS apart from symptom management. Addressing this, a novel potential therapeutic avenue utilizing small interference RNAs (siRNA) has been designed. By targeting the conserved EBNA-1 gene sequences in EBV types 1 and 2, five potential siRNAs were identified in our analysis. Thorough evaluations encompassing off-target binding, thermodynamics and secondary structure elucidation, efficacy prediction, siRNA-mRNA sequence binding affinity exploration, melting temperature, and docking of siRNAs with human argonaute protein 2 (AGO2) were conducted to elucidate the siRNAs efficiency. These designed siRNA molecules harnessed promising silencing activity in the EBNA-1 gene encoding the EBNA-1 antigen protein and thus have the potential to mitigate the severity of this dangerous virus.

Predicting Plasmodium falciparum kinase inhibitors from antimalarial medicinal herbs using computational modeling approach.

Malaria remains a significant public health challenge, with resistance to available drugs necessitating the development of novel therapies targeting invasion-dependent proteins. Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK-1) is essential for host erythrocyte invasion and parasite asexual development. This study screened a library of 490 compounds using computational methods to identify potential PfCDPK-1 inhibitors. Three compounds; 17-hydroxyazadiradione, Picracin, and Epicatechin-gallate derived from known antimalarial botanicals, showed potent inhibitory effects on PfCDPK-1. These compounds exhibited better binding affinities (-8.8, -9.1, -9.3 kCal/mol respectively), pharmacokinetics, and physicochemical properties than the purported inhibitory standard of PfCDPK-1, Purfalcamine. Molecular dynamics simulations (50 ns) and molecular mechanics analyses confirmed the stability and binding rigidity of these compounds at the active pocket of PfCDPK-1. The results suggest that these compounds are promising pharmacological targets with potential therapeutic effects for malaria treatment/management without undesirable side effects. Therefore, this study provides new insights into the development of effective antimalarial agents targeting invasion-dependent proteins, which could help combat the global malaria burden. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00175-z.

Exploring the nuclear proteins, viral capsid protein, and early antigen protein using immunoinformatic and molecular modeling approaches to design a vaccine candidate against Epstein Barr virus.

The available Epstein Barr virus vaccine has tirelessly harnessed the gp350 glycoprotein as its target epitope, but the result has not been preventive. Right here, we designed a global multi-epitope vaccine for EBV; with special attention to making sure all strains and preventive antigens are covered. Using a robust computational vaccine design approach, our proposed vaccine is armed with 6-16 mers linear B-cell epitopes, 4-9 mer CTL epitopes, and 8-15 mer HTL epitopes which are verified to induce interleukin 4, 10 & IFN-gamma. We employed deep computational mining coupled with expert intelligence in designing the vaccine, using human Beta defensin-3-which has been reported to induce the same TLRs as EBV-as the adjuvant. The tendency of the vaccine to cause autoimmune disorder is quenched by the assurance that the construct contains no EBNA-1 homolog. The protein vaccine construct exhibited excellent physicochemical attributes such as Aliphatic index 59.55 and GRAVY - 0.710; and a ProsaWeb Z score of - 3.04. Further computational analysis revealed the vaccine docked favorably with EBV indicted TLR 1, 2, 4 & 9 with satisfactory interaction patterns. With global coverage of 85.75% and the stable molecular dynamics result obtained for the best two interactions, we are optimistic that our nontoxic, non-allergenic multi-epitope vaccine will help to ameliorate the EBV-associated diseases-which include various malignancies, tumors, and cancers-preventively.