Hsp90 Inhibitors as New Leads To Target Parasitic Diarrheal Diseases

Author:

Debnath Anjan,Shahinas Dea,Bryant Clifford,Hirata Ken,Miyamoto Yukiko,Hwang Grace,Gut Jiri,Renslo Adam R.,Pillai Dylan R.,Eckmann Lars,Reed Sharon L.,McKerrow James H.

Abstract

ABSTRACTEntamoeba histolyticaandGiardia lambliaare anaerobic protozoan parasites that cause amebiasis and giardiasis, two of the most common diarrheal diseases worldwide. Current therapy relies on metronidazole, but resistance has been reported and the drug has significant adverse effects. Therefore, it is critical to search for effective, better-tolerated antiamebic and antigiardial drugs. We synthesized several examples of a recently reported class of Hsp90 inhibitors and evaluated these compounds as potential leads for antiparasitic chemotherapy. Several of these inhibitors showed strongin vitroactivity against bothE. histolyticaandG. lambliatrophozoites. The inhibitors were rescreened to discriminate between amebicidal and giardicidal activity and general cytotoxicity toward a mammalian cell line. No mammalian cytotoxicity was found at >100 μM for 48 h for any of the inhibitors. To understand the mechanism of action, a competitive binding assay was performed using the fluorescent ATP analogue bis-ANS (4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid dipotassium salt) and recombinantE. histolyticaHsp90 preincubated in both the presence and absence of Hsp90 inhibitors. There was significant reduction in fluorescence compared to the level in the control, suggesting thatE. histolyticaHsp90 is a selective target. Thein vivoefficacy and safety of one Hsp90 inhibitor in a mouse model of amebic colitis and giardiasis was demonstrated by significant inhibition of parasite growth at a single oral dose of 5 mg/kg of body weight/day for 7 days and 10 mg/kg/day for 3 days. Considering the results forin vitroactivity andin vivoefficacy, Hsp90 inhibitors represent a promising therapeutic option for amebiasis and giardiasis.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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