Siccanin is a novel selective inhibitor of trypanosomatid complex ii (succinate-ubiquinone reductase) and a potent broad-spectrum anti-trypanosomatid drug candidate

Abstract

Trypanosomiasis and leishmaniasis, neglected tropical diseases caused by protozoan trypanosomatid parasites, result in heavy socioeconomic impact. Currently available drugs are old with, narrow spectrum, and unreliable. We recently reported that the pathogen of American trypanosomiasis, Trypanosoma cruzi, has a noncanonical mitochondrial complex II (succinate-quinone oxidoreductase: SQR) that comprises 12-subunits and displays poor sensitivities to mammalian SQR inhibitors. Because their orthologs are only conserved in the genome of trypanosomatids, the SQR is a drug target candidate. Herein, we searched for selective inhibitors of trypanosomatid SQR by using the nonpathogenic trypanosomatid Leishmania tarentolae enzyme as model. Nano LC-MS/MS and biochemical studies revealed the SQRs of L. tarentolae and T. cruzi have similar subunits composition and sensitivity to established quinone-site SQR inhibitors. Further, we performed screening for selective LtSQR inhibitors and found that the old fungicidal compound siccanin, with an IC50 value of 190 nM, is presently the most potent trypanosomatid SQR inhibitor. Interestingly, it showed negligible inhibition against porcine SQR (selectivity index: 4,500-fold) but displayed mixed-type inhibition against quinone with Ki1 and Ki2 of 39 and 102 nM, respectively. Notably, siccanin specifically targets complex II and spares other quinone-utilizing enzymes of the respiratory chain. Siccanin is not species-specific; it inhibited SQR of T. cruzi, T. brucei, and L. donovani with IC50 of up to 0.368 lM. Remarkably, it caused in vitro growth inhibition across the clinically relevant forms of the major trypanosomatid parasites at IC50 of 0.7–13 lM, and hence is a potential broad-spectrum drug candidate against trypanosomatids.