Targeting RNA lifelines-PIN domain endonucleases for broad-spectrum antitrypanosomal drug development

Authors: Arun HS Kumar

Ger. J. Microbiol. 2026. vol. 6, Iss. 3 pp:1-9
Doi: https://doi.org/10.51585/gjm.2026.3.0066

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Abstract:

Trypanosomal infections present a significant threat to human and veterinary health, with current treatments constrained by toxicity, emerging resistance, and a predominant focus on DNA-targeting mechanisms. Most available drugs primarily target kinetoplast or nuclear DNA, underscoring the need for alternative molecular targets. PIN domain-containing proteins, which serve as essential endonucleases in RNA processing and ribosome biogenesis, constitute a promising and largely unexplored target class across trypanosome species. Nine PIN domain-containing proteins from various trypanosome species, along with the human homolog SMG6, were selected from the UniProt database based on structural annotation. Full-length protein structures predicted by AlphaFold were analyzed to identify binding pockets using computational tools. The highest-ranked binding pockets were subjected to comparative sequence alignment to identify conserved motifs. Subsequently, eight established drugs and one investigational compound were assessed for binding affinity against all targets using molecular docking. Binding pocket analysis revealed considerable variability in pocket number and quality, with ESB3 exhibiting the highest druggability score. Sequence alignment identified conserved acidic motifs, including EADDTN- and DIDIL-like patterns, indicative of catalytic and metal-binding functions. Molecular docking demonstrated that compounds such as BIBR1532, triptolexhibitenzalutamide, displayed strong binding affinities, particularly to ESB2 and ESB3 proteins. However, certain compounds also exhibited comparable affinity for the human SMG6 protein, underscoring the importance of selectivity. These findings identify PIN domain-containing proteins as novel and potential targets for antitrypanosomal drug development. Targeting RNA-processing pathways rather than DNA offers a mechanistically distinct and potentially effective strategy to address resistance. The identification of high-affinity compounds and conserved functional motifs supports the feasibility of developing broad-spectrum therapeutics.

Keywords:

Trypanosomes, PIN domain proteins, RNA processing, Molecular docking, Drug repurposing, Broad-spectrum antitrypanosomal agents

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