Cathepsin C (CatC) is a lysosomal cysteine protease implicated in the pathophysiology of inflammatory diseases and cancer metastasis, representing a crucial therapeutic target. Despite the therapeutic potential of protease modulation, the inhibitory activity of pentacyclic triterpenoids against CatC has not been previously explored. This study provides the kinetic characterization of oleanolic (OA) and ursolic acids (UA) as competitive inhibitors of CatC. Kinetic analysis revealed that OA exhibits superior inhibitory potency (IC50 = 41.35 µM) compared to its structural isomer UA (IC50 = 112.10 µM), suggesting that the methyl group position within the triterpene scaffold significantly influences binding affinity. Furthermore, the methanolic extract of Solidago virgaurea demonstrated inhibitory activity with an IC₅₀ of 0.467 mg/mL. Effect-directed profiling using HPTLC quantified the OA content (3.952 µg/mg extract) and allowed for the calculation of its molar contribution to the extract's total activity. The theoretical IC50 of the extract, expressed as OA equivalent (4.04 µM), was significantly lower than the experimental IC50 of pure OA, indicating a potential synergistic effect or the presence of other potent inhibitors within the complex matrix. While HPTLC-ABTS+• profiling confirmed the presence of antioxidant constituents in the extract, pure OA and UA showed no direct radical scavenging activity under the conditions applied, pointing to a specific mechanism of action like modulating the activity of enzymes involved in the development of oxidative stress. These findings identify S. virgaurea as a promising source of CatC inhibitors and establish oleanane-type triterpenoids as lead scaffolds for the development of novel inhibitors.
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