Fungal leucyl-tRNA synthetase (LeuRS)

Fungal leucyl-tRNA synthetase (LeuRS) is an essential enzyme that catalyzes the attachment of leucine to its cognate tRNA, a critical step in protein biosynthesis (UniProt, 2024). The enzyme features a specialized connective polypeptide 1 (CP1) domain, which serves as an editing site to ensure translational fidelity by hydrolyzing mischarged tRNAs, such as those incorrectly linked to isoleucine (Rock et al., 2007, Science). This editing domain is a validated therapeutic target for antifungal agents, most notably the oxaborole class of drugs (Baker et al., 2006, J. Med. Chem.). The drug tavaborole inhibits the enzyme by forming a stable covalent adduct with the 3'-terminal adenosine of tRNA-Leu within the CP1 editing site, a mechanism known as oxaborole tRNA-trapping (OBORT) (PubMed, 2023). This trapping prevents the release of tRNA and halts protein synthesis, leading to fungal cell death. Due to structural divergence between fungal and human LeuRS editing domains, drugs targeting this site exhibit high selectivity and low toxicity (FDA, 2014). This target is primarily relevant in the treatment of fungal infections such as onychomycosis and other dermatomycoses.

Other names

Leucine--tRNA ligaseCP1 editing domainLARSLeuSLeucyl-tRNA synthetase editing domain

Inhibition of protein synthesis via the oxaborole tRNA-trapping (OBORT) mechanism, where the drug forms a stable covalent adduct with the terminal adenosine of tRNA-Leu in the CP1 editing site, preventing further aminoacylation.