Halofuginone HBr | Prolyl-tRNA synthetase inhibitor

Halofuginone (64924-67-0) is a potent and selective prolyl-tRNA synthetase (PRS) inhibitor (K_i=18.3 nM) derived from febrifugine.¹ Also attenuates TGF-β signaling, including reversibly reducing Smad3 protein levels and inhibiting fibroblast differentiation.² Blocks fibrosis, angiogenesis, and tumor progression.^2,3 Inhibition of PRS results in amino acid starvation which activates the integrated stress response (ISR) and mTOR signaling⁴ and thus preventing differentiation of T_H17 cells, suppressing the autoimmune response⁵. Reduces TMPRSS2 protein levels via enhanced ubiquitination and proteasomal degradation, limiting SARS-CoV-2 cellular entry.⁶

References/Citations:

1. Keller et al. (2012), Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase; Nat. Chem. Biol., 8 311
2. Nelson et al. (2012), Halofuginone down-regulates Smad3 expression and inhibits the TGß-induced expression of fibrotic markers in human corneal fibroblasts; Mol. Vis., 18 479
3. Elkin et al. (2000), Halofuginone: a potent inhibitor of critical steps in angiogenesis progression. FASEB J., 14 2477
4. Misra et al. (2021), Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress; Nucleic Acids Res., 49 5726
5. Sundrud et al. (2009), Halofuginone inhibits Th17 cell differentiation by activating the amino acid starvation response; Science, 324 1334
6. Chen et al. (2021), A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry; Nat. Commun., 12 3907