VNI cures acute and chronic experimental Chagas disease.
Chagas disease is a deadly infection caused by the protozoan parasite Trypanosoma cruzi. Afflicting approximately 8 million people in Latin America, Chagas disease is now becoming a serious global health problem proliferating beyond the traditional geographical borders, mainly because of human and vector migration. Because the disease is endemic in low-resource areas, industrial drug development has been lethargic. The chronic form remains incurable, there are no vaccines, and 2 existing drugs for the acute form are toxic and have low efficacy. Here we report the efficacy of a small molecule, VNI, including evidence of its effectiveness against chronic Chagas disease. VNI is a potent experimental inhibitor of T. cruzi sterol 14α-demethylase. Nontoxic and highly selective, VNI displays promising pharmacokinetics and administered orally to mice at 25 mg/kg for 30 days cures, with 100% cure rate and 100% survival, the acute and chronic T. cruzi infection.
Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, TN, USA.
Fernando
F
Villalta
Mark C
MC
Dobish
Pius N
PN
Nde
Yulia Y
YY
Kleshchenko
Tatiana Y
TY
Hargrove
Candice A
CA
Johnson
Michael R
MR
Waterman
Jeffrey N
JN
Johnston
Galina I
GI
Lepesheva
D000284:Administration, Oral; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy*; D002908:Chronic Disease; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D010069:Oxadiazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016019:Survival Analysis; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D007093:Imidazoles; D010069:Oxadiazoles; C578921:VNI compound
Chagas disease; Trypanosoma cruzi; VNI; drug discovery; inhibition; sterol 14alpha-demethylase (CYP51); sterol biosynthesis