Targeting parasites for destruction
Scientists discover an Achilles’ heel in trypanosoma family of parasites responsible for sleeping sickness and Chagas disease
Trypanosoma are parasitic one-celled eukaryotic organisms most commonly known for causing devastating sleeping sickness (trypanosoma brucei) and Chagas disease (trypanosoma cruzi) in humans. Similar to malaria’s plasmodium species, these parasites have several stages in their life cycle, which includes blood-sucking insects like the Tsetse-fly (sleeping sickness) and the assassin-bug (Chagas) and are thus hard to control.
Furthermore, these parasites do not only pose danger to humans but also to livestock-animals like cattle. To add insult to injury, trypanosoma
[..] are becoming increasingly resistant to currently available medications (4–6). Chagas disease has been most prevalent in South America but is spreading internationally owing to increased migration (7, 8) and potential climate change–induced vector spreading (9–11). The drug discovery pipeline for trypanosomiases is thin. Existing medications (Suramin, Pentamidine, Melarsoprol, Benznidazole, and Nifurtimox) have serious side effects, require long treatment schedules, and often fail to eliminate parasitemia.
To summarize the above; all prospects look grim for us but good for the parasites.
In the world of microorganisms, this is nothing new, they have been fighting the evolutionary battle for billions of years and they have gotten really good at it. Yet, from vaccinations against viruses to antibiotics against bacteria, by intensive studying we scientists were able to come up with solutions to improve human health and keep danger at bay. One remarkable insight we gained from studying bacteria was that their cells would sometimes use unique pathways or proteins to perform certain essential functions. These bacteria-specific processes can be targeted for destruction by specific molecules while the same molecules are harmless to our mammalian cells; today we know them as antibiotics.
Imagine this simplicity. The whole beauty of antibiotics is that they are blocking the “gas engine” that keeps bacterial cells running while our cells run on solar batteries and have no idea what a gas engine is even for.
Antibiotic resistance arises once bacteria figure out ways how to change their gas engine designs, but they will likely never be able to change to solar power (= develop a new molecular pathway).
The basic research that led to the discovery of the fundamental molecular differences between bacteria and human cells was the stepping stone which enabled the design of life-altering modern antibiotics.
Vaccination and development of antibiotics are the two major medical breakthroughs that doubled human lifespan in the last 150 years, before that, the biggest killer of humanity was not cancer or cardiovascular disease, but infectious diseases.
With parasites, history might repeat itself
Sleeping sickness and Chagas disease are enormous problems for the developing world; the Swiss Drugs-for-Neglected-Diseases-initiative (DNDi) estimates that Chagas alone infects around 6 million people every year with huge economic burden for many countries. Even worse, sleeping sickness is usually deadly if untreated and more than 13 million people are at risk in rural areas in Africa. It is a sad but fair assessment that parasites still have a major impact on the life expectancy and economic prosperity in developing countries.
Luckily, this might change for the better soon.
Half a century ago, basic researchers discovered special organelles (=cellular subunits like mitochondria or lysosomes) in trypanosoma parasites called “glycosomes”; structures somewhat related to human peroxisomes. Recently, it has been shown that these glycosomes are the “gas engine” of trypanosoma, meaning that their proper functioning is essential to keep the parasites running. The most important protein family for glycosomes are peroxins (PEX), membrane proteins that regulate formation of glycosomes as well as transport of cargo in and out of these organelles. The interaction of two members of that family, PEX14 and PEX5, have been shown to be critical for this process and siRNA mediated knockdown of PEX14 made glucose become toxic for the parasites. 50 years after discovery and almost 2 decades after intensive basic research, scientists finally gained enough understanding of the parasite’s “gas engine” design to know where they have to break it.
Spearheaded by a group of German scientists from the Helmholz Center and the Technical University in Munich, efforts to develop a small molecule inhibitor against this essential trypanosoma organelle finally bear fruit. Using a technique called NMR spectroscopy, the scientists investigated the molecular structure of the PEX14-PEX5 interacting domain; basically zooming in where and how these two proteins touch.
Once the shape and atoms involved in PEX14-PEX5 interaction became clear, Davidowski and colleagues set out to design a molecule that would block this interaction. Having structural information about proteins allows researchers to build 3D models in silico and to virtually test chemical compounds for a perfect fit; commonly known by scientists as “compound screening” and “3D docking” experiments.
Once candidate compounds arise out of these virtual efforts, the scientists went on to validate these molecules in a real-world trypanosoma. They assessed how the inhibition correlates with parasite toxicity, pharamcological parameters like EC50 values as well as metabolic profile of parasites exposed to sub-lethal drug inhibition.
Finally, the authors could show convincingly what has been speculated about and searched for a long time: An Achilles heel in the “gas engine” of trypanosoma parasites.
Here, we show that disrupting the PEX14-PEX5 interaction with small molecule inhibitors leads to accumulation of glycosomal enzymes in the cytosol, adenosine triphosphate (ATP) depletion, glucose toxicity, and metabolic collapse resulting in T. brucei parasite death.
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Our proof-of-concept study shows that trypanosomal protein-protein interactions are attractive drug targets and open the way for further clinical development of PEX14 inhibitors.
Once again, the collaborative work of our greatest human endeavor, called science, is at the verge of improving the lives and prospects of millions of fellow humans. It is important to support basic science and scientific inquiry; for without the work done by countless scientists to study trypanosoma, discover their unique subunits and characterize all proteins involved, this study would have been impossible.
After all, you do not start building a castle at the top; you carefully lay the foundations to build upon first. This achievement was half a century in the making, who knows what basic research today will achieve in a century to come?
This story is part of advances in biological sciences, a science communication platform that aims to explain ground-breaking science in the field of biology, medicine, biotechnology, neuroscience and genetics to literally everyone. Scientific understanding has too much barriers, let’s break them down!
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