Aims: Malaria deaths occur primarily due to complicated malaria associated with the sequestration of Plasmodium falciparum-infected erythrocyte (PfIE) in the capillary microvasculature. This study aims to design peptide ligand conjugates (PLCs) for treating complicated malaria using various in silico techniques. The PLC includes a natural ligand for the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1): expressed explicitly on the surface of PfIE, and a highly immunogenic peptide derived from the commonly used peptide vaccines in malaria-endemic countries. The ligand is predicted to prevent the sequestration of PfIE, and the peptide is predicted to eliminate PfIE from circulation by the pre-existing vaccine-induced immunity.
Main methods: The epitope identification from the vaccines and the analysis of physicochemical properties, antigenicity, allergenicity, and toxicity were performed using SVMTriP, ProtParam, VaxiJen, AllerTop, and ToxinPred servers, respectively. The high throughput virtual screening (HTVS) and drug-like properties analysis of natural compound ligands were carried out by Schrodinger-2021 software. The molecular dynamics simulations were performed through the WebGro server.
Key findings: HTVS revealed three bioactive natural ligands for PfEMP1 from (NPASS) database. Three super immunogenic peptides were identified from malaria-endemic countries' commonly used peptide vaccines. Finally, Nine PLCs were designed with different combinations of peptides and ligands with the suitable non-cleavable triazole linker.
Significance: Antimalarials have been losing efficacy in a time when malaria deaths in 2020 significantly increased than in 2019. In this scenario, further research on the designed PLCs may offer some innovative immune therapeutics for complicated malaria with minimum possibilities of drug resistance.
Keywords: Complicated malaria; EMP1; HTVS; Immunotherapy; Parasite sequestration; Peptide ligand conjugates.
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