The mechanism of the most commonly used antimalarial drugs unveiled

For centuries, quinoline has been an effective compound in antimalarial drugs, although no one knew its mode of action in vivo.

Today, a team led by the Weizmann Institute has discovered its mechanism in infected red blood cells in near-native conditions, by using the ESRF, Alba Synchrotron and BESSY. They publish their results in PNAS.

Malaria remains one of the biggest killers in low-income countries. Estimates of the number of deaths each year range from 450,000 to 720,000, with the majority of deaths happening in Africa. In the last two decades, the malaria parasite has evolved into drug-resistant strains. “Recently, the increasing geographical spread of the species, as well as resistant strains has concerned the scientific community, and in order to improve antimalarial drugs we need to know how they work precisely”, explains Sergey Kapishnikov, from the University of Copenhagen, in Denmark, and the Weizmann Institute, in Israel, and leader of the study.

Plasmodium parasite, when infecting a human, invades a red blood cell, where it ingests hemoglobin to grow and multiply. Hemoglobin releases then iron-containing heme molecules, which are toxic to the parasite. However, these molecules crystallise into hemozoin, a disposal product formed from the digestion of blood by the parasite that makes the molecules inert. For the parasite to survive, the rate at which the heme molecules are liberated must be slower or the same as the rate of hemozoin crystallization. Otherwise there would be an accumulation of the toxic heme within the parasite.

>Read more on the ESRF website

Image (taken from BESSY II article): The image shows details such as the vacuole of the parasites (colored in blue and green) inside an infected blood cell.
Credit:
S. Kapishnikov

Two other institutes, BESSY II at HZB and ALBA Synchrotron, have participated in this research. Please find here their published articles:

> X-ray microscopy at BESSY II reveal how antimalaria-drugs might work

> The mechanism of the most commonly used antimlalarial drugs in near- native conditions unveiled

Killing two parasites with one stone

Each year Malaria affects 219 million people, causing almost half a million deaths. Crysptosporidiosis is the leading cause of diarrheal diseases in infants, leading to 200,000 deaths a year. An international team of scientists, led by researchers at the University of Dundee, have discovered a molecule which clears the parasites that cause these two illnesses. Their results are published in PNAS.

Malaria is a well-known disease caused by the parasites Plasmodium falciparum and Plamodium vivax and is the target of many available medications. However, the development of drug resistance has led the scientific community search for new therapeutic molecules which might provide for chemoprotection, prevention of transmission, and the treatment of relapsing malaria.
Like malaria, cryptosporidiosis is also a disease caused parasites, in this case Cryptosporidium hominis and Cryptosporidium parvum. Although it does not have the same ‘visibility as Malaria, Cryptosporidiosis is the leading cause worldwide of moderate-to-severe diarrheal diseases in infants and is estimated to lead to more than 200,000 deaths a year. The disease and is also associated with malnutrition, stunted growth, and cognitive-development problems in children. The currently approved drug, nitazoxanide, has poor efficacy, particularly in the case of immune-compromised patients and malnourished children, where there is no effective treatment.

>Read more on the ESRF website

Image: Binding modes of ligands bound to PfKRS1 and CpKRS. (A) PfKRS1:Lys:2 showing the binding mode of 2 (C atoms, gold) bound to the ATP site of PfKRS1 (PDB ID code 6AGT) superimposed upon PfKRS1:Lys:cladosporin (cladosporin C atoms, slate; PDB ID code 4PG3). (B) PfKRS1:5 showing binding mode of 5 bound to PfKRS1 (PDB ID code 6HCU). (See the full image: here)

New research helps pursuit for malaria vaccine

Scientists from The Hospital for Sick Children (SickKids) identify structure of key malaria protein

Using technology available at the Canadian Light Source synchrotron, SickKids scientists have taken an important step forward on the path to finding effective biomedical interventions to halt the spread of malaria, a disease that affected an estimated 216 million people worldwide in 2016 alone.

Jean-Philippe Julien, a scientist in the Molecular Medicine program at SickKids, and his colleagues focused on a molecule known to be essential for the malaria parasite Plasmodium falciparum to go through the sexual stages of its lifecycle. Disrupting that stage of the lifecycle has the potential to reduce infections and deaths from malaria because parasite transmission between humans would be blocked by inhibiting parasite development in the Anopheles mosquito.

“The protein we looked at was identified several years ago as an important target for malaria parasite biology,” says Julien, who is also a Canada Research Chair in Structural Immunology and an Assistant Professor in the Departments of Biochemistry and Immunology at the University of Toronto. “The field has tried for over a decade to clarify its structure in order to guide the development of biomedical interventions that can curb the spread of malaria.”

>Read more on the Canadian Light Source website

Image: One of the structures of the malaria protein (orange) being recognized by the humanized blocking antibody (green and blue).

Structures reveal new target for malaria vaccine

The discovery paves the way for the development of a more effective and practical human vaccine for malaria, a disease responsible for half a million deaths worldwide each year.

Malaria kills about 445,000 people a year, mostly young children in sub-Saharan Africa, and sickens more than 200 million. It’s caused by a parasite, Plasmodium falciparum (Pf), and is spread to humans through the bite of an infected Anopheles mosquito.

The parasite’s complex life cycle and rapid mutations have long challenged vaccine developers. Only one experimental vaccine, known as RTS,S, has progressed to a Phase 3 clinical trial (testing on large groups of people for efficacy and safety). To elicit an immune response, this vaccine uses a fragment of circumsporozoite protein (CSP), which covers the malaria parasite in its native conformation. However, the trial results showed that RTS,S is only moderately effective, protecting about one-third of the young children who received it over a period of four years.

>Read more on the Advanced Light Source website.

Image (a) Left: Surface representation of CIS43 (light chain in tan and heavy chain in light blue), with peptide 21 shown as sticks (purple). Right: A 90° rotation of the representation. See entire image here.

Fighting malaria with X-rays

Today 25 April, is World Malaria Day.

Considered as one of humanity’s oldest life-threatening diseases, nearly half the world population is at risk, with 216 million people affected in 91 countries worldwide in 2016. Malaria causes 445 000 deaths every year, mainly among children. The ESRF has been involved in research into Malaria since 2005, with different techniques being used in the quest to find ways to prevent or cure the disease.

Malaria in humans is caused by Plasmodium parasites, the greatest threat coming from two species: P. falciparum and P. vivax. The parasites are introduced through the bites of infected female Anopheles mosquitoes. They travel to the liver where they multiply, producing thousands of new parasites. These enter the blood stream and invade red blood cells, where they feed on hemoglobin (Hgb) in order to grow and multiply. After creating up to 20 new parasites, the red blood cells burst, releasing daughter parasites ready for new invasions. This life cycle leads to an exponential growth of infected red blood cells that may cause the death of the human host.

The research carried out over the years at the ESRF has aimed to identify mechanisms critical for the parasite’s survival in the hope of providing an intelligent basis for the development of drugs to stop the parasite’s multiplication and spread.

>Read more on the European Synchrotron website

Image: Inside the experimental hutch of the ESRF’s ID16A nano-analysis beamlin.
Credit: Pierre Jayet

Hijacker parasite blocked from infiltrating blood

A major international collaboration led by Melbourne researchers has discovered that the world’s most widespread malaria parasite infects humans by hijacking a protein the body cannot live without.

The researchers were then able to successfully develop antibodies that disabled the parasite from carrying out this activity.
The study, led by the Walter and Eliza Hall Institute’s Associate Professor Wai-Hong Tham and Dr Jakub Gruszczyk, found that the deadly malaria parasite Plasmodium vivax (P. vivax) causes infection through latching onto the human transferrin receptor protein, which is crucial for iron delivery into the body’s young red blood cells.

Published today in Science, the discovery has solved a mystery that researchers have been grappling with for decades.
The MX and SAXS beamline staff at the Australian Synchrotron assisted with data collection.

Associate Professor Tham, who is also a HHMI-Wellcome International Research Scholar, said the collective efforts of teams from Australia, New Zealand, Singapore, Thailand, United Kingdom, United States, Brazil and Germany had brought the world closer to a potential effective vaccine against P.vivax malaria.

>Read more on the Australian Synchrotron website

 

Malaria in Action

Seeing the invisible

In 2007 Helen Saibil was at a conference in Australia. Amongst the presentations there happened to be talks on the parasites malaria and toxoplasma and how they infect mammalian cells, causing disease. Helen is a structural biologist and whilst listening she began to realise that her newly acquired skills -she was doing electron tomography of cells- might allow the researchers to see things they had never seen before.

Electron tomography reveals structures in the interiors of cells in great detail. What she hoped was that it could be used to look at the malaria parasites inside red blood cells [See images below] to get a better understanding of what they do there. Helen approached one of the speakers, Mike Blackman, then at the National Institute for Medical Research at Mill Hill in London, and so began a thriving collaboration. One that has produced the remarkable pictures of malaria parasites breaking out of infected human red blood cells on this page.

Helen Saibil and her colleagues used electron tomography to peer into malaria infected cells, looking at the parasites hiding and multiplying inside. The technique produces exquisitely detailed pictures able to reveal very tiny features, but it has one big drawback. Electrons cannot penetrate deep into the sample so it only works on very thinly sliced samples, much thinner than an individual cell. As a result it cannot be used to look at entire cells, or in this case red blood cells containing malaria parasites.

>Read more on the Diamond Light Source website

 

New insights about malaria parasites infection mechanisms

Unraveled details about how the malaria parasite acts after invading the red blood cells.

This highlight has been possible thanks to two advanced microscope techniques combination: X-ray fluorescence microscopy and soft X-rays tomography, this one conducted in ALBA Synchrotron. Infected red blood cells image analysis offer new information that could yield new drugs design against malaria, an illness that claims over 400.000 lives each year.
Plasmodium falciparum causes the malaria disease. This parasite, transmitted through mosquito sting, infects red blood cells of its victim. Once inside, it uses hemoglobin (the protein in charge of oxygen transport) as a nutrient. When it is digested, iron is released in a form of heme molecules. These heme molecules are toxic to the parasite, but it has a strategy to make them harmless: it packs heme in pairs and finally they are packed forming hemozoin crystals. In this way, poisonous iron is locked up and no longer will be a threat for the parasite.


>Read More on the ALBA website

Infographic: Model for biochemistry processes that occur inside the parasite. The parasite takes the hemoglobin from the red blood cell (RBC)
1 and digests it inside the digestive vacuole (DV)
2. as a consequence, heme groups are released
3. and HDP protein packages them in pairs (heme dimers)
4. finally, in the crystallization process these dimers are converted in hemozoin crystals
5. blue arrow points out the suggested feedback mechanism that regulates hemoglobin degradation.