8 research outputs found
Synthesis and antiplasmodial activity of highly active reverse analogues of the antimalarial drug candidate fosmidomycin
Mechanism of Allosteric Inhibition of the Enzyme IspD by Three Different Classes of Ligands
Enzymes
of the nonmevalonate pathway of isoprenoid biosynthesis
are attractive targets for the development of herbicides and drugs
against infectious diseases. While this pathway is essential for many
pathogens and plants, mammals do not depend on it for the synthesis
of isoprenoids. IspD, the third enzyme of the nonmevalonate pathway,
is unique in that it has an allosteric regulatory site. We elucidated
the binding mode of phenylisoxazoles, a new class of allosteric inhibitors.
Allosteric inhibition is effected by large conformational changes
of a loop region proximal to the active site. We investigated the
different roles of residues in this loop by mutation studies and identified
repulsive interactions with Asp291 and Asp292 to be responsible for
inhibition. Crystallographic data and the response of mutant enzymes
to three different classes of allosteric inhibitors provide an in-depth
understanding of the allosteric mechanism. The obtained mutant enzymes
show selective resistance to allosteric inhibitors and provide conceptually
valuable information for future engineering of herbicide-resistant
crops. We found that the isoprenoid precursors IPP and DMAPP are natural
inhibitors of <i>Arabidopsis thaliana</i> IspD; however,
they do not seem to bind to the allosteric site
Mechanism of Allosteric Inhibition of the Enzyme IspD by Three Different Classes of Ligands
Enzymes
of the nonmevalonate pathway of isoprenoid biosynthesis
are attractive targets for the development of herbicides and drugs
against infectious diseases. While this pathway is essential for many
pathogens and plants, mammals do not depend on it for the synthesis
of isoprenoids. IspD, the third enzyme of the nonmevalonate pathway,
is unique in that it has an allosteric regulatory site. We elucidated
the binding mode of phenylisoxazoles, a new class of allosteric inhibitors.
Allosteric inhibition is effected by large conformational changes
of a loop region proximal to the active site. We investigated the
different roles of residues in this loop by mutation studies and identified
repulsive interactions with Asp291 and Asp292 to be responsible for
inhibition. Crystallographic data and the response of mutant enzymes
to three different classes of allosteric inhibitors provide an in-depth
understanding of the allosteric mechanism. The obtained mutant enzymes
show selective resistance to allosteric inhibitors and provide conceptually
valuable information for future engineering of herbicide-resistant
crops. We found that the isoprenoid precursors IPP and DMAPP are natural
inhibitors of <i>Arabidopsis thaliana</i> IspD; however,
they do not seem to bind to the allosteric site
α-Substituted β-Oxa Isosteres of Fosmidomycin: Synthesis and Biological Evaluation
Specific inhibition of enzymes of the non-mevalonate
pathway is
a promising strategy for the development of novel antiplasmodial drugs.
α-Aryl-substituted β-oxa isosteres of fosmidomycin with
a reverse orientation of the hydroxamic acid group were synthesized
and evaluated for their inhibitory activity against recombinant 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) of Plasmodium falciparum and for their <i>in vitro</i> antiplasmodial activity against chloroquine-sensitive and resistant
strains of P. falciparum. The most
active derivative inhibits IspC protein of P. falciparum (<i>Pf</i>IspC) with an IC<sub>50</sub> value of 12 nM
and shows potent <i>in vitro</i> antiplasmodial activity.
In addition, lipophilic ester prodrugs demonstrated improved P. falciparum growth inhibition <i>in vitro</i>
IspC as Target for Antiinfective Drug Discovery: Synthesis, Enantiomeric Separation, and Structural Biology of Fosmidomycin Thia Isosters
The emergence and spread of multidrug-resistant
pathogens are widely
believed to endanger human health. New drug targets and lead compounds
exempt from cross-resistance with existing drugs are urgently needed.
We report on the synthesis and properties of “reverse”
thia analogs of fosmidomycin, which inhibit the first committed enzyme
of a metabolic pathway that is essential for the causative agents
of tuberculosis and malaria but is absent in the human host. Notably,
IspC displays a high level of enantioselectivity for an α-substituted
fosmidomycin derivative