Daily Archives: 26.01.2016

A New Approach to Malaria Treatment?

  • Author: Angewandte Chemie International Edition
  • Published Date: 21 January 2014
  • Source / Publisher: Angewandte Chemie International Edition/Wiley-VCH
  • Copyright: Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Targeting the Non-Mevalonate Terpene Biosynthetic Pathway

Two of the most urgent challenges for scientists are the battles against food shortages and infectious diseases like malaria. Unfortunately, both the herbicides used to protect plants and the anti-infectives that shield us from disease rapidly lose their effectiveness as the target organisms develop resistance. In order to benefit both fields at once, scientists tested lead compounds from agrochemical research against infectious germs as well. In this way, a team of German and Swiss researchers has found a new candidate that may work against malaria, as they report in the journal Angewandte Chemie.

“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 from the ETH Zurich, Switzerland. “This biosynthetic pathway is found in many human pathogens and in plants, but does not occur in mammals.” Correspondingly, an inhibitor should only have a toxic effect on pathogens and plants, not humans. 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 have now discovered new inhibitors and characterized the ways in which they work.

Pseudilins Inhibit Enzyme IspD

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 of the aforementioned non-mevalonate terpene biosynthetic pathway – and found several hits. The most interesting compounds are pseudilins, highly halogenated alkaloids from marine bacteria, and have a significant inhibitory effect on IspD, as researchers at the TU Munich led by Michael Groll demonstrated in NMR-based tests and researchers at the University of Hamburg led by Markus Fischer showed in photometric tests. Says Groll: “Interestingly, the chemical scaffold of the pseudilins is completely different from that of a previously discovered IdpD inhibitor. This suggests that the mode of action should also be different.”

To research this mechanism, Andrea Kunfermann from Groll’s team synthesized cocrystals of the pseudilins and IspD enzymes and examined them by X-ray crystallography. This showed that the pseudilins bind to an allosteric pocket in the enzyme. Halogen atoms in the pseudilins build up halogen bridges to the enzyme, which are, in addition to metal-ion coordination, responsible for the strong binding. Occupation of this pocket changes the shape of the enzyme so that a cosubstrate required for proper functioning of the enzyme can no longer dock at the binding site in the active center.

“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,” reports Diederich. The researchers hope to use this as a new starting point for malaria treatment.

Pseudilins: Halogenated, Allosteric Inhibitors of the Non-Mevalonate Pathway Enzyme IspD. Andrea Kunfermann, Matthias Witschel, Boris Illarionov, René Martin, Matthias Rottmann, H. Wolfgang Höffken, Michael Seet, Wolfgang Eisenreich, Hans-Joachim Knölker, Markus Fischer, Adelbert Bacher, Michael Groll, François Diederich.
Angew. Chem. Int. Ed. 2014.
DOI: 10.1002/anie.201309557

A Trojan Horse for Cancer Cells

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Author: Angewandte Chemie International Edition
Published Date: 19 January 2016
Source / Publisher: Angewandte Chemie International Edition/Wiley-VCH
Copyright: Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Killing Tumor Cells with a Fenton Reaction

Amorphous iron nanoparticles have a specific toxicity in tumor cells. In the journal Angewandte Chemie, Chinese scientists describe their design and synthesis of a special amorphous state of nanoparticulate iron, which can locally release reactive iron species in the acidic and hydrogen peroxide rich environment of cancer cells, providing new possibilities for theranostics and chemodynamic therapies.

Cancer cells are characterized by their relatively acidic cell environment and their production of significant amounts of hydrogen peroxide compared to healthy cells. Some chemodynamic approaches for cancer treatment thus employ the Fenton reaction, that is, iron ions reacting with the hydrogen peroxide to produce reactive oxygen species (ROS), which in turn can damage and destroy the cancer cells. However, the transport of iron ions to the target cells is problematic, and crystalline iron nanoparticles are not as effective.

Amorphous Iron Nanoparticles with Unique Properties

Jianlin Shi and Wenbo Bu and their groups at Shanghai Institute of Ceramics, in collaboration with Fudan University of Shanghai, China, have now prepared iron nanoparticles in an amorphous, glassy state. “Interestingly, the amorphous iron(0) nanoparticles present several unique physicochemical properties,” the scientists write, and: “The results confirm that the amorphous iron nanoparticles, hydrogen peroxide, and acidic conditions act synergistically to kill cells.”

In addition to their potential as drugs, other advantages are a good contrast for magnetic resonance imaging and the possibility of magnetic targeting. “Ideally, a perfect carrier should release its cargo at once when it is transferred from neutral to mildly acidic conditions, such as those in the tumor microenvironment,” the authors write. Using magnetic resonance imaging, they proved by in vitro and in vivo tests that the anticipated mechanism was working.

Magnetic targeting, on the other hand, enables drug delivery to the target tissue through magnetization. The scientists observed that “efficient magnetic targeting and retention had been achieved in vivo, providing a good basis for chemodynamic therapy.” However, they also say that future prospects will include surface modification of the particles to further improve the tumor-targeting performance. In a nutshell, Shi and Bu’s elegant “hubble bubble” approach, as they call it, has produced a tiny, highly effective Trojan horse for chemodynamic cancer therapy, as shown in mice. The preparation method features mild conditions and has prospects for other metals as well.

Synthesis of Iron Nanometallic Glasses and Their Application in Cancer Therapy by a Localized Fenton Reaction.
Chen Zhang, Wenbo Bu, Dalong Ni, Shenjian Zhang, Qing Li, Zhenwei Yao, Jiawen Zhang, Heliang Yao, Zheng Wang, Jianlin Shi.
Angew. Chem. Int. Ed 2016.    DOI: 10.1002/anie.201510031

 

Messenger of Death

Author: Anne Deveson
Published Date: 21 January 2016
Source / Publisher: Chemistry – A European Journal/Wiley-VCH
Copyright: Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Breast cancer is the most commonly diagnosed malignancy and the deadliest among women worldwide. An interesting field in cancer-fighting research is immunotherapy, which does not aim to directly eliminate cancer cells, but to activate and enhance the immune system’s action against tumours.

In this field, Ramón Martínez-Máñez, University of València, Spain, Ana M. Jiménez-Lara, Instituto de Investigaciones Biomédicas A. Sols CSIC-UAM, Spain, and their collaborators are interested in the use of ligands for Toll-like receptors (TLRs) to potentiate immune stimulatory pathways. They designed a delivery system based on mesoporous silica nanoparticles capped with synthetic double stranded RNA (dsRNA) polyinosinic–polycytidylic acid. The nanoparticles were loaded with doxorubicin, a commonly used chemotherapeutic agent.

The team found that these dsRNA-conjugated nanoparticles can effectively target TLR3-expressing breast cancer cells. They cause a TLR3-mediated internalization of the nanoparticles that correlates with a caspase-dependent apoptosis (cell death) induction.

Targeting Innate Immunity with dsRNA-Conjugated Mesoporous Silica Nanoparticles Promotes Anti-Tumor Effects on Breast Cancer Cells.
Amelia Ultimo, Cristina Giménez, Pavel Bartovsky, Elena Aznar, Felix Sancenon, M. Dolores Marcos, Pedro Amorós, Ana R. Bernardo, Ramón Martínez-Máñez, Ana María JIménez-Lara, Jose R. Murguía,
Chem. Eur. J. 2015. DOI: 10.1002/chem.201504629