%0 Generic
%A Sanchez, Laura
M.
%A Knudsen, Giselle M.
%A Helbig, Claudia
%A Muylder, Geraldine De
%A Mascuch, Samantha M.
%A Mackey, Zachary B.
%A Gerwick, Lena
%A Clayton, Christine
%A McKerrow, James H.
%A Linington, Roger G.
%D 2016
%T Examination
of the Mode of Action of the Almiramide Family of Natural Products
against
the Kinetoplastid Parasite Trypanosoma brucei
%U https://acs.figshare.com/articles/dataset/Examination_of_the_Mode_of_Action_of_the_Almiramide_Family_of_Natural_Products_against_the_Kinetoplastid_Parasite_i_Trypanosoma_brucei_i_/2420512
%R 10.1021/np300834q.s002
%2 https://ndownloader.figshare.com/files/4062262
%K Leishmania donovani
%K probe
%K membrane assembly machinery
%K glycosome function
%K African trypanosomiasis
%K Natural Products
%K target identification studies
%K almiramide C
%K brucei lysates
%K organelle
%K kinetoplastid parasites
%K perturb glycosomal function
%K vivo zebrafish model
%K epifluorescence microscopy
%K micromolar activity
%K parasite survival
%K zebrafish neuromast cells
%K agent
%K Kinetoplastid Parasite Trypanosoma bruceiAlmiramide C
%K parasite Trypanosoma brucei
%K compound series
%K organism development
%K development candidates
%K site localization
%K side effect
%K bloodstream stage
%K Almiramide Family
%X Almiramide C is a marine natural
product with low micromolar activity
against Leishmania donovani, the causative agent
of leishmaniasis. We have now shown that almiramide C is also active
against the related parasite Trypanosoma brucei,
the causative agent of human African trypanosomiasis. A series of
activity-based probes have been synthesized to explore both the molecular
target of this compound series in T. brucei lysates
and site localization through epifluorescence microscopy. These target
identification studies indicate that the almiramides likely perturb
glycosomal function through disruption of membrane assembly machinery.
Glycosomes, which are organelles specific to kinetoplastid parasites,
house the first seven steps of glycolysis and have been shown to be
essential for parasite survival in the bloodstream stage. There are
currently no reported small-molecule disruptors of glycosome function,
making the almiramides unique molecular probes for this understudied
parasite-specific organelle. Additionally, examination of toxicity
in an in vivo zebrafish model has shown that these
compounds have little effect on organism development, even at high
concentrations, and has uncovered a potential side effect through
localization of fluorescent derivatives to zebrafish neuromast cells.
Combined, these results further our understanding of the potential
value of this lead series as development candidates against T. brucei.
%I ACS Publications