Monaghan P, Fardis M, Revill WP, Bell A.Antimalarial effects
of macrolactones related to FK520 (ascomycin) are independent of
the immunosuppressive properties of the compounds.
J Infect Dis. 2005 Apr 15;191(8):1342-9.
Department of Microbiology, Moyne Institute of Preventive
Medicine, Trinity College, Dublin 2, Ireland.
The polyketide macrolactone FK506 inhibits the growth of
Plasmodium falciparum in culture and the enzymatic (peptidyl-prolyl
cis-trans isomerase [PPIase]) and chaperone activities of a
recently identified P. falciparum FK506-binding protein
(PfFKBP35). However, the potent immunosuppressive properties of
FK506 exclude it from consideration as an antimalarial drug. We
describe the antimalarial actions of the related compound FK520
and a number of its nonimmunosuppressive analogues. All
compounds were shown to be strong inhibitors of parasite growth,
regardless of their immunosuppressive potency. Although some of
the compounds inhibited the PPIase activity of recombinant
PfFKBP35, they all inhibited the chaperone activity of this
bifunctional protein. These findings suggest that the
antimalarial effects of this class of drug may be mediated via
inhibition of the chaperone activity rather than via the
enzymatic activity of PfFKBP35. Elucidating the precise
intracellular functions of PfFKBP35 may facilitate the design of
more potent inhibitors that retain their specificity for
parasite target protein.
PMID: 15776382 |
