Resourceful Enzyme-Activated Compounds based on Alkoxyamine scaffold for the Treatment of parasitic diseases – REACT

Neglected tropical diseases (NTDs) affect millions of people worldwide, mainly in tropical and subtropical regions. These diseases, caused by a variety of pathogens and toxins, have serious health consequences as well as significant social and economic impacts. They mainly affect poor communities. It is estimated that over a billion people are affected by NTDs, while 1.6 billion require preventive and curative interventions to combat them. Among the most common NTDs are parasitic diseases such as malaria, trypanosomiasis, leishmaniasis, amoebiasis and schistosomiasis. The increasing spread of drug resistance is seriously compromising eradication policies, raising further concerns about the control of these diseases. Due to climate change, NTDs are expected to move from tropical and subtropical zones to higher latitudes.
Malaria and leishmaniasis are caused respectively by the protozoa Plasmodium and Leishmania, transmitted to humans by the bite of infected mosquitoes or sandflies. The treatment of these diseases is complex due to the life cycles of the pathogens, which often involve vectors and large animal reservoirs. Contrary to optimistic forecasts of malaria eradication by 2030, the number of cases continues to rise, with around 247 million cases and 619,000 deaths in 2021. Artemisinin-based combination therapies are the first-line treatments for uncomplicated forms of malaria. Artemisinin resistance in P. falciparum has spread to Asia, South America and Africa. Leishmaniasis is treated with drugs such as antimonials, miltefosine, paromomycin and amphotericin B, but resistance is also becoming a growing concern. Treatment failures for these diseases are frequent, underlining the urgency of the search for new antiparasitic drugs capable of eliminating resistant parasites.
The REACT project is based on the chemical properties of radical species for the treatment of these diseases. It involves the preparation of a stable pro-drug (blocked alkoxyamine), activated on demand by essential parasite enzymes to produce labile, unlocked alkoxyamines, capable of spontaneously homolyzing into highly reactive alkyl radicals at physiological temperature. These radicals trigger irreparable damage in parasites. The activation of alkoxyamines is targeted by parasite-specific enzymes, an approach that differs from conventional inhibition of enzymatic activity. This concept has emerged as a powerful and versatile approach.
An innovative feature of this project is the generation of free radicals on demand, a mechanism which should limit the emergence of resistance. Unlike conventional drugs, which exert selective pressure on specific molecular pathways, the radicals generated by this approach act randomly, making it more difficult for parasites to develop resistance mechanisms. The project involves the design of broad-spectrum pro-drugs, capable of targeting various stages of the parasite life cycle.
In summary, this project aims to develop new drugs against malaria and leishmaniasis by preparing highly stable alkoxyamines, activated by specific parasite enzymes to give unstable alkoxyamines, and to test their efficacy in vitro and then in mouse models. This represents a potential breakthrough in circumventing drug resistance and offering new therapeutic options for NTDs.