{"id":18227,"date":"2018-08-17T12:00:00","date_gmt":"2018-08-17T12:00:00","guid":{"rendered":"https:\/\/dev.inrs.ca\/inrs-takes-aim-at-the-dreaded-tropical-disease-leishmaniasis\/"},"modified":"2020-11-05T12:01:41","modified_gmt":"2020-11-05T17:01:41","slug":"inrs-takes-aim-at-the-dreaded-tropical-disease-leishmaniasis","status":"publish","type":"post","link":"https:\/\/dev.inrs.ca\/en\/news\/inrs-takes-aim-at-the-dreaded-tropical-disease-leishmaniasis\/","title":{"rendered":"INRS takes aim at the dreaded tropical disease leishmaniasis"},"content":{"rendered":"\n

Researchers in medicinal chemistry and parasitology develop an innovative strategy to identify leishmanicidal molecules.<\/strong><\/p>\n\n\n\n

Leishmania<\/em> is a microorganism that enters the human body via a sandfly bite. Instead of fleeing the white blood cells deployed by the immune system to destroy it, the parasite allows itself to be swallowed up. In doing so, Leishmania<\/em> has developed the ideal strategy for continuing its life cycle, threatening the health of over 500 million people at risk of crossing its path in Africa, Europe, Asia, and the Americas. <\/p>\n\n\n\n

\"\"
The insect vectors of Leishmania are in the family of phlebotomine sandflies. Credits: Center for Disease Control and Prevention.
<\/figcaption><\/figure><\/div>\n\n\n\n

Leishmaniasis, the disease caused by the parasite, has been on the radar of scientists for a long time, not only because of efforts to find treatment, but because the parasite makes an ideal model for study. Hence, numerous immune mechanisms have been elucidated by researchers thanks to the disease, including at INRS. However, the quest for affordable and effective treatment continues. INRS professors Albert Descoteaux<\/a> and Steven LaPlante<\/a> have developed a new, cost-effective strategy to rapidly identify molecules capable of eliminating Leishmania<\/em>, a disease which can disfigure, disable, or kill its victims, especially in tropical areas.<\/p>\n\n\n\n

A disease affecting numerous species<\/strong><\/h2>\n\n\n\n

 \u201cI have been studying this parasite for 30 years, and there is still a lot we do not understand,\u201d says parasitologist Albert Descoteaux, who works to uncover the secrets of Leishmania<\/em>, a genus encompassing some 20 single-celled species. In addition to its human victims, the parasite also targets some 70 other mammal species, according to the World Health Organization. Leishmania<\/em> moves from an host to another by hitching a ride with tiny phlebotomine sandflies, which transmit the undesirable parasite when they bite.<\/p>\n\n\n\n

\"\"
Amastigote and promastigote form of Leishmania seen in electron microscopy. Credit: Zephyris on Wikimedia
<\/figcaption><\/figure><\/div>\n\n\n\n

According to the most recent estimates, 12 million people are currently affected by one form of leishmaniasis or another. There are three main forms: cutaneous, mucocutaneous, and visceral. \u201cThese are diseases that destroy lives\u2014when they do not kill outright,\u201d stresses Professor Descoteaux, adding that the pharmaceutical companies have little interest in developing treatments. \u201cThere is little commercial interest in neglected tropical diseases like leishmaniasis,\u201d he points out. \u201cIt is the second-leading parasitic killer in the world, right behind malaria, yet there has been no real headway made on treatments in decades. There is currently no effective vaccine, and the available treatments all have major shortcomings, including serious side effects, high cost, and problems administering them in endemic areas.\u201d He pauses before adding, \u201cUnfortunately, as is the case with many other drugs, the parasite is also developing resistance. That is never good news.\u201d<\/p>\n\n\n\n

Albert Descoteaux, who is based at Centre INRS-Institut Armand-Frappier, is one of five INRS professors currently working on leishmaniasis. Their efforts to better understand the fundamental interaction between the parasite and its host account for one-third of all research activity on the disease in Canada, and their work is recognized worldwide. <\/p>\n\n\n\n

Professor Steven LaPlante, who has been with INRS since 2015, specializes in drug discovery. With his colleague Albert Descoteaux, he has developed a project to identify new molecules that show promise for treating leishmaniasis. Their innovative approach is raising hopes of finding a more effective tool for developing drugs for leishmaniasis, but also for many other diseases.<\/p>\n\n\n\n

The challenge of finding the right target<\/strong><\/h2>\n\n\n\n

Having evolved its tactics and molecular machinery over millions of years, Leishmania<\/em> has more than one trick up its sleeve. This is why there are so many obstacles to identifying molecules capable of eliminating the disease. For one thing, unicellular protists like Leishmania<\/em> have more in common with mammal cells than with bacteria and viruses. \u201cLike fungus, yeast, and worms, Leishmania<\/em> are complex cells with a nucleus, and they have similarities to human cells,\u201d notes the professor. <\/p>\n\n\n\n

\u201cBut they have taken a different evolutionary path, so there are lots of differences we need to identify and understand.\u201d<\/p><\/blockquote>\n\n\n\n

Second, delivering a useful molecule to the parasite is a challenge. \u201cBefore it can kill Leishmania<\/em>, the drug has to get past all kinds of barriers,\u201d explains LaPlante.\u201d It has to penetrate the infected cell without killing it or being too toxic. Then it has to reach and enter the protist to do its thing. Let\u2019s just say that there are a lot of molecules to test before we find the right one for the job!\u201d <\/p>\n\n\n\n

Testing a lot of molecules is exactly the approach used by most researchers in the drug discovery process, but it takes extensive resources. Unfortunately, in the fight against leishmaniasis, there is little financial incentive for funding this kind of work. Yet given the prevalence of the disease worldwide, there are numerous calls for urgent action to find new treatments.<\/p>\n\n\n\n

A promising new approach<\/strong><\/h2>\n\n\n\n

This is the context in which the two INRS researchers joined forces, drawing on their combined expertise in biology (Albert Descoteaux) and medicinal chemistry (Steven LaPlante). LaPlante has access to a special small-molecule library from which he selected 1,604 molecules that had the best chances of reaching Leishmania<\/em> in the macrophages and preventing it from completing its life cycle. Compared to the molecule libraries maintained by pharmaceutical companies\u2014which can hold up to two million molecules\u2014his library represents a very modest number but have special properties which makes it easily manageable within the confines of a university research lab.<\/p>\n\n\n\n

\"\"
Infected macrophages with amastigotes of Leishmania donovani. Credits: Christine Matte, Albert Descoteaux Laboratory, INRS<\/figcaption><\/figure><\/div>\n\n\n\n

\u201cWe dubbed our approach Fragment-Based Phenotypic Lead Discovery, or FPLD,\u201d says Professor LaPlante. \u201cIt\u2019s a combination of tried and tested methods that hadn\u2019t previously been adapted for leishmaniasis. We start by administering very small molecules to cultured cells and then observe the impact on the infection.\u201d <\/p>\n\n\n\n

In medicinal chemistry, several phases are required to develop a drug with multiple characteristics. The ideal molecule for fighting an infection should be non-toxic to humans, easy to administer, capable of reaching the infectious agent, affordable to produce, and, obviously, effective against the pathogen in question.<\/p>\n\n\n\n

As is the case when designing any everyday object, different components of a drug are selected to perform different jobs. The components in question are molecular fragments. The goal of the two INRS professors was to identify which of these could stop Leishmania<\/em> in its tracks. The idea is that effective fragments can be combined with other components serving various purposes\u2014stability, delivery, absorption, and so on\u2014to improve efficacy and end up with a viable drug. <\/p>\n\n\n\n

“We\u2019ve been very fortunate to be able to rely on our collaborator NMX Research and Solutions Inc. and General Manager Fran\u00e7ois Bilodeau who donated all the molecules we needed for our study. It\u2019s a huge contribution,\u201d notes Professor LaPlante. NMX designed the molecular fragments at the INRS business incubator, where the young startup is based. <\/p>\n\n\n\n

A painstaking job<\/strong><\/h2>\n\n\n\n

Yann Ayotte, lead author on the study recently published on the project<\/a>, systematically\u2014and very patiently\u2014observed cultures treated with the fragments under the microscope, counting the number of parasites in the infected cells in order to compare them. The PhD student, who is currently continuing his research in Professor LaPlante\u2019s lab, first joined the project as an intern in Albert Descoteaux\u2019s lab at the end of his undergraduate degree. The two professors are quick to praise his outstanding dedication to his work.<\/p>\n\n\n\n

After numerous experiments, the highly targeted screening of a small number of molecules allowed the team to identify two families of molecules showing high efficacy against Leishmania<\/em>: indole and indazole derivatives. A dozen molecules have shown good potential, a very high number compared to other screening techniques.<\/p>\n\n\n\n

Is there a new drug on the horizon? \u201cFor now, we are still at the very beginning of the process,\u201d says Professor Descoteaux. \u201cAnd you can\u2019t skip any steps!\u201d adds LaPlante. First, it\u2019s essential to understand why the molecules have a leishmanicidal effect, a task that will keep Professor Descoteaux busy for a good while yet. In the mean time, the active molecule can be improved upon and \u201cdressed up\u201d with other appendages in order to fulfil all the criteria of an effective treatment\u2014a job for Professor LaPlante and his team. <\/p>\n\n\n\n

A broader vision<\/strong><\/h2>\n\n\n\n

For Steven LaPlante, the most successful aspect of the project so far has been to show that a university lab can help identify potential new avenues for treatment. Pharmaceutical research does not cover all diseases or types of intervention, and from this perspective, academia can also play an important role. <\/p>\n\n\n\n

The work of the team garnered enough enthusiasm that the journal ChemMedChem<\/a><\/em>, published by ChemPubSoc Europe, a partnership of European chemical societies, rated it as a \u201cVery Important Paper\u201d and put it on the cover of the issue in which it appeared. <\/p>\n\n\n\n

What will the study on the modes of action of the molecules identified at INRS reveal? <\/p>\n\n\n\n

\u201cResearch on Leishmania has lifted the veil on several properties of immune system we would not have been able to observe any other way. Every time there is a new avenue to explore, we add to our knowledge on the immune system and on the biology of this parasite. Even if a new drug is still a long way away, these molecules will help us hone our understanding of the disease, which will keep us busy for years to come.\u201d<\/p>Albert Descoteaux, professor<\/cite><\/blockquote>\n","protected":false},"excerpt":{"rendered":"

Researchers in medicinal chemistry and parasitology develop an innovative strategy to identify leishmanicidal molecules.<\/p>\n","protected":false},"author":1,"featured_media":9411,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[185,688],"tags":[],"sectors":[146,679],"class_list":["post-18227","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-innover-a-linrs","category-innover-a-linrs-en","sectors-sante","sectors-sante-en"],"acf":[],"yoast_head":"\nINRS takes aim at the dreaded tropical disease leishmaniasis | INRS<\/title>\n<meta name=\"description\" content=\"Researchers in medicinal chemistry and parasitology develop an innovative strategy to identify leishmanicidal molecules.\" \/>\n<meta name=\"robots\" content=\"noindex, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<meta property=\"og:locale\" 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