A combination of peptides and antibiotics may result in a more effective treatment for leishmaniasis

A combination of peptides and antibiotics could be a key for fighting Leishmania parasites and avoiding the toxicity caused by current drugs to people and animals. CSIC scientists have participated in this research that opens the door to new and more effective treatments against leishmaniasis.

Promastigotes of the Leishmania donovani parasite observed by confocal microscopy (UAB)

Leishmaniasis is caused by the protozoan Leishmania parasites which are transmitted by the bite of an infected sandfly. Although in rich countries this disease mainly affects dogs, in other countries it can cause great damage on the health of humans, causing from ulcers to damage to the bone marrow, liver or spleen, all of which could be fatal.

The WHO estimates that there are currently over one billion people living in areas where leishmaniasis is endemic and that there are over one million new cases each year. Therefore there is an urgent need to find new, efficient and selective alternatives drugs to reduce the adverse side effects of existing drugs such as paromomycin and miltefosine.

A work with the participation of the CSIC, and led by the UAB, has found out a new strategy to fight Leishmania. The study is led by professors Rosa Maria Ortuño and Ona Illa, from the UAB Department of Chemistry; and it has the participation of Luis Rivas from the Margarita Salas Biological Research Center of the CSIC; Míriam Royo, from the CSIC Institute of Advanced Chemistry of Catalonia; Jean-Didier Maréchal, from the same Department of the UAB; and Carme Nogués, from the Department of Cell Biology, Physiology and Immunology at the UAB.

The study consisted in the preparation and biological evaluation of new cell-penetrating peptides (CPPs) which, together with an antibiotic conjugation, serve as a vehicle for the drug, enabling it to enter the parasite's cell membrane and be released inside, thus causing its death. The treatment is very effective and a low number of oral doses of the drug are needed. In addition, the synthesised CPPs are toxic for Leishmania but not for mammal cells. “Although the idea of using CPPs in the treatment of leishmaniasis is not unknown, the importance of this study lies in its high cell-penetrating capacity and the selectivity (mammal vs parasite cells) of the new synthesised and studied peptides”, explains Rosa Maria Ortuño.

In particular, the research has served to study peptides made up of non-protein amino acids with a covalent conjugate of doxorubicin (Dox), a drug which is also used in cancer treatments. While Dox in its free form is not active when incubated with Leishmania because it is not capable of penetrating its interior, the Dox-PPC conjugate has demonstrated to be toxic in very low concentrations (≥1 mM). Its cell-penetrating capacity has been rationalised through molecular modelling studies. The results are highly promising, although research is still needed "before thinking about new drugs, but we are now a little bit closer of our objective", Ortuño says.

Original article:

Ona Illa et al., Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery SystemsInternational Journal of Molecular Sciences. 2020, 21, 7502; doi:10.3390/ijms21207502