Pseud's corner: NMR assesses pseudilins

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  • Published: Feb 1, 2014
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Pseud's corner: NMR assesses pseudilins

Antimalalarial weedkiller

Understanding more clearly a major enzymatic biosynthetic route to isoprenoid compounds - the non-mevalonate pathway - could offer targets to researchers for new types of herbicides for crop protection as well as agents against infectious diseases, including malaria. NMR assays and other techniques have now been used to assist in the assessment of the pseudilins. Credit: Angew/Wiley

Understanding more clearly a major enzymatic biosynthetic route to isoprenoid compounds - the non-mevalonate pathway - could offer targets to researchers for new types of herbicides for crop protection as well as agents against infectious disease, including malaria. NMR assays and other techniques have now been used to assist in the assessment of the pseudilins.

Food security and the fight against infectious disease are two of the most pressing problems facing science and technology today, perhaps they always were. Unfortunately, as is becoming increasingly apparent, both the herbicides used to protect crop plants from being overgrown by weeds and invasive species and the anti-infective agents, the pharmaceuticals that protect us or treat human disease are prone to the evolution of resistance in the target species whether weed or microbe. However, certain classes of biologically active compounds have efficacy in both domains. They can kill weeds as well as parasites, for instance. In order to benefit both fields at once, scientists often test lead compounds against agrochemical and disease targets.

Now, a team from Germany and Switzerland have taken this approach to new levels and identified herbicidal compounds that may be a new drug candidate that is possibly active against the malaria parasite. They report details in the journal Angewandte Chemie.

Inhibition

"Recently, enzymes from the non-mevalonate terpene biosynthetic pathway have been identified as attractive target structures with novel modes of activity for the development of herbicides and drugs against infectious diseases," explains François Diederich of the Swiss Federal Research Institute, ETH Zurich. "This biosynthetic pathway is found in many human pathogens and in plants, but does not occur in mammals," he adds. As such, there are only a few sites in the human body or in other mammals that would be affected by inhibitors disrupting the biochemistry of this pathway and so should be minimally toxic to people, since their toxic effects only appear in the pathogens and weed targets.

Diederich and his co-workers at the ETH, TU Munich, BASF-SE, the University of Hamburg, the Swiss Tropical Institute STPHI in Basel, and TU Dresden, Germany, have not only identified such new inhibitors they have used NMR and other techniques to assay and characterize these compounds to identify the mode of action.

By using high-throughput screening methods, the researchers of BASF SE led by Matthias Witschel tested about 100,000 compounds for an inhibitory effect against plant IspD, an enzyme in the non-mevalonate terpene biosynthetic pathway. They found a clutch of hits among which the most interesting compounds were the pseudilins. These compounds are highly halogenated natural alkaloids present in marine bacteria and displayed a potent inhibitory effect on IspD. TU Munich's Michael Groll and his colleagues applied NMR-based tests while researchers at the University of Hamburg led by Markus Fischer used photometric tests to home in on the compounds' properties. "Interestingly, the chemical scaffold of the pseudilins is completely different from that of a previously discovered IspD inhibitor," Groll says. "This suggests that the mode of action should also be different."

Mode of action

Andrea Kunfermann in Groll's team co-crystallised the pseudilins and IspD enzymes and examined them using X-ray diffraction in order to home in on a possible mechanism. The XRD data revealed that the pseudilins bind to an allosteric pocket in the enzyme. Apparently, the presence of the halogen atoms that pepper the skeleton allow bridges to be built between molecule and enzyme, which, in addition to metal ion coordination, is responsible for the strong binding interaction and thus the potency of the compound as an inhibitor. The team explains that the presence of the inhibitor distorts the enzyme's active pocket so that the co-substrate required for full functionality cannot bind, thus completely crippling the enzyme and blocking the biosynthetic pathway.

"The pseudilins demonstrated herbicidal activity in plant assays and were active against Plasmodium falciparum, the pathogen that causes Malaria tropica and is dependent on the non-mevalonate biosynthesis pathway for survival," Diederich adds. The compounds might thus act as a starting point for the development of new antimalarial drugs.

Related Links

Angew Chem Int Edn, 2014, 45, 32-40: "Pseudilins: Halogenated, Allosteric Inhibitors of the Non-Mevalonate Pathway Enzyme IspD"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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