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bioRxiv · 10.64898/2026.11.04.764270

RNA-targeted aminopyridine compounds provide a new antifungal strategy

Hwang, J.·Sisto, L. J.·Shi, T.·Van Zandt, M. C.·Pyle, A. M.
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Abstract

While RNA is an emerging therapeutic target class, progress is limited by a shortage of well-defined targets in which ligand binding is coupled to measurable function. The group I intron, a self-splicing ribozyme essential in fungal mitochondria but absent from humans, offers both a tractable platform for exploring first principles of small molecule-RNA targeting and a selective antifungal target. We recalibrated an intron-splicing assay to approximate cellular conditions and performed an extensive, cryo-EM-guided structure-activity relationship campaign against the Candida albicans mtLSU intron. Ligands containing a flexible diamine outperformed conformationally constrained analogues, suggesting a general principle for engaging dynamic RNA surfaces and yielding lead aminopyridine 56 (IC 21.6 nM). Compound 56 synergizes with amphotericin B against C. albicans, suggesting a path for combination therapies. RT-qPCR confirmed direct target engagement in cells. This work establishes the fungal group I intron as a viable, mechanistically distinct antifungal target and a model platform for RNA-targeted discovery.

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Hwang, J., Sisto, L. J., Shi, T., Van Zandt, M. C., Pyle, A. M.. 2026-11-06. RNA-targeted aminopyridine compounds provide a new antifungal strategy. https://doi.org/10.64898/2026.11.04.764270

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