Investigators Use Innovative Approach to Explore New Treatment Options for Leishmaniasis
Investigators have developed an innovative method to identify molecules capable of eliminating the Leishmania parasite.
Leishmaniasis is a vector-borne disease caused by at least 20 different species of an intracellular parasite transmitted by more than 30 species of sandflies. Over 70 animal species have been found as natural reservoir hosts of Leishmania parasites.
An estimated 700,000 to 1 million new cases of Leishmaniasis occur each year and subsequently there are between 20,000 to 30,000 deaths reported annually, according to the World Health Organization.
In a new study from Institut National de la Recherche Scientifique (INRS), published in ChemMedChem, investigators developed a new strategy to identify the molecules that could be capable of eliminating the parasite.
The first line of treatment for leishmaniasis has been antimonies like sodium stibogluconate, which, according to the investigators, can cause severe side effects and has been linked to high levels of antibiotic resistance. Other drugs such as miltefosin, amphotericin B, and paromomycin have been designated to treat the disease, but are associated with toxicity, high costs, require hospitalization, and can also lead to antibiotic resistance.
For their study, a team of investigators led by Albert Descoteaux, PhD, professor at INRS and Steven LaPlante, PhD, professor of medicinal chemistry at University of Quebec INRS, set out to identify new molecules for treating leishmaniasis.
To do this, the investigators created a method called Fragment-Based Phenotypic Lead Discovery (FPLD). This method is based on Fragment-based lead discovery (FBLD) which “screens small collections of low-molecular-weight compounds to identify binders to target proteins from which larger drug-like compounds can be designed.” The method also borrows concepts from phenotypic-based lead discovery (PLD) to create an overall quicker method of screening molecules.
The investigators selected 1604 molecules that they anticipated would have the best chance of reaching Leishmania in the macrophages and intervening prior to the completion of the parasite’s life cycle.
The molecules were counterscreened against bone-marrow derived macrophages to eliminate cytotoxicity for the macrophages. Then the remaining molecules were tested on macrophages of a Leishmania-infected macrophage to determine which molecules would remain active against intracellular parasites.
Overall, the investigators were able to identify 2 families of molecules that demonstrate efficacy against Leishmania—indole and indazole. These fragments demonstrated activity similar to sodium stibogluconate and had no observable toxicity on macrophages. Additionally, no evidence of compound aggregation was observed.
“For now, we are still at the very beginning of the process,” Dr. Descoteaux said in a recent statement. Dr. Descoteaux’s team will continue to work on gaining a better understanding of why the molecules have a leishmanicidal effect, while Dr. LaPlante’s team works on “dressing up” the active molecule with other appendages to fulfill criteria of an effective treatment.
This approach can enable institutions to launch new drug discovery projects where FPLD can identify new targets for neglected diseases, according to the investigators.