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TitlePotent Tetrahydroquinolone Eliminates Apicomplexan Parasites.
Journal, issue, pagesFront Cell Infect Microbiol, Vol. 10, Page 203, Year 2020
Publish dateJun 9, 2020
AuthorsMartin J McPhillie / Ying Zhou / Mark R Hickman / James A Gordon / Christopher R Weber / Qigui Li / Patty J Lee / Kangsa Amporndanai / Rachel M Johnson / Heather Darby / Stuart Woods / Zhu-Hong Li / Richard S Priestley / Kurt D Ristroph / Scott B Biering / Kamal El Bissati / Seungmin Hwang / Farida Esaa Hakim / Sarah M Dovgin / Joseph D Lykins / Lucy Roberts / Kerrie Hargrave / Hua Cong / Anthony P Sinai / Stephen P Muench / Jitender P Dubey / Robert K Prud'homme / Hernan A Lorenzi / Giancarlo A Biagini / Silvia N Moreno / Craig W Roberts / Svetlana V Antonyuk / Colin W G Fishwick / Rima McLeod /
PubMed AbstractApicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a ...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 inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces tachyzoites and encysted bradyzoites , and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant . Causal prophylaxis and radical cure are achieved after 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.
External linksFront Cell Infect Microbiol / PubMed:32626661 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution3.5 - 3.8 Å
Structure data

EMDB-11002:
CryoEM structure of bovine cytochrome bc1 in complex with a tetrahydroquinolone inhibitor
Method: EM (single particle) / Resolution: 3.8 Å

PDB-6xvf:
Crystal structure of bovine cytochrome bc1 in complex with tetrahydro-quinolone inhibitor JAG021
Method: X-RAY DIFFRACTION / Resolution: 3.5 Å

Chemicals

ChemComp-PG4:
TETRAETHYLENE GLYCOL / precipitant*YM / Polyethylene glycol

ChemComp-6PE:
1,2-DIHEXANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE

ChemComp-PO4:
PHOSPHATE ION / Phosphate

ChemComp-CDL:
CARDIOLIPIN / phospholipid*YM / Cardiolipin

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE / Heme B

ChemComp-LMT:
DODECYL-BETA-D-MALTOSIDE / detergent*YM

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM / Discrete optimized protein energy

ChemComp-JAG:
2-methyl-3-[4-[4-(trifluoromethyloxy)phenoxy]phenyl]-5,6,7,8-tetrahydro-3~{H}-quinolin-4-one

ChemComp-HEC:
HEME C / Heme C

ChemComp-FES:
FE2/S2 (INORGANIC) CLUSTER / Iron–sulfur cluster

ChemComp-PX4:
1,2-DIMYRISTOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DMPC, phospholipid*YM / Dimyristoylphosphatidylcholine

ChemComp-HOH:
WATER / Water

Source
  • bos taurus (cattle)
KeywordsMEMBRANE PROTEIN / Cytochrome bc1 / Malaria / Electron transport

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