Data_Sheet_1_Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites.pdf
Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria.
History
References
- https://doi.org//10.1107/S2052252518001616
- https://doi.org//10.1093/bioinformatics/btu638
- https://doi.org//10.1107/S0907444910048675
- https://doi.org//10.1073/pnas.1416611112
- https://doi.org//10.1093/clinids/21.3.656
- https://doi.org//10.1186/s13071-018-2983-5
- https://doi.org//10.1186/1471-2164-15-515
- https://doi.org//10.1111/cmi.12735
- https://doi.org//10.3109/09273948.2011.564068
- https://doi.org//10.1073/pnas.1208069109
- https://doi.org//10.1107/S0907444904019158
- https://doi.org//10.1107/S0907444910007493
- https://doi.org//10.1107/S090744491003982X
- https://doi.org//10.1074/jbc.M313866200
- https://doi.org//10.1016/S0076-6879(08)04417-0
- https://doi.org//10.1128/AAC.06450-11
- https://doi.org//10.1021/jm3007596
- https://doi.org//10.1021/acsinfecdis.7b00062
- https://doi.org//10.1128/AAC.47.1.309-316.2003
- https://doi.org//10.1371/journal.pone.0014057
- https://doi.org//10.1128/AAC.01607-06
- https://doi.org//10.1128/AAC.42.9.2284
- https://doi.org//10.1038/nmeth.3317
- https://doi.org//10.1056/NEJMoa1710775
- https://doi.org//10.1021/ci200227u
- https://doi.org//10.1107/S090744491200251X
- https://doi.org//10.1056/NEJMoa1802537
- https://doi.org//10.1186/s13059-014-0550-8
- https://doi.org//10.1093/cid/ciw356
- https://doi.org//10.1186/1475-2875-13-2
- https://doi.org//10.1097/01.inf.0000202070.59190.9a
- https://doi.org//10.1038/srep29179
- https://doi.org//10.1128/AAC.01183-15
- https://doi.org//10.1107/S0907444906053625
- https://doi.org//10.1016/j.ijpara.2019.02.007
- https://doi.org//10.1107/S0907444911001314
- https://doi.org//10.1038/s41598-017-10675-6
- https://doi.org//10.1017/S0031182017002050
- https://doi.org//10.1016/j.parint.2012.12.003
- https://doi.org//10.1016/j.ajo.2008.04.033
- https://doi.org//10.1073/pnas.0802982105
- https://doi.org//10.1186/1475-2875-12-212
- https://doi.org//10.1186/s12936-016-1145-5
- https://doi.org//10.1002/0471250953.bi0813s47
- https://doi.org//10.1073/pnas.0506580102
- https://doi.org//10.2471/BLT.12.111732
- https://doi.org//10.1645/0022-3395(2005)091[0484:HMPICC]2.0.CO;2
- https://doi.org//10.1074/jbc.273.47.31040
- https://doi.org//10.1590/S0037-86822002000100001
- https://doi.org//10.1093/cid/cit032
- https://doi.org//10.1242/dev.02541
- https://doi.org//10.1128/mBio.01155-15
- https://doi.org//10.1056/NEJM196906122802402
- https://doi.org//10.1073/pnas.1609482113
- https://doi.org//10.1038/nmeth.4193
CC BY 4.0