Ubiquitin proteasome system as a target potential for antimalarials

Parasites of the genus Plasmodium are responsible for causing malaria in humans. Strains resistant to all available antimalarials can be found in various locations around the world, including parasites resistant to the latest generation of combined drugs, such as piperaquine + artemisinin. Plasmodium develops between two completely different hosts, being a vertebrate and the vector mosquito, and thus has the ability to adapt to extreme environments. Through the complex life cycle in the hosts, Plasmodium invades and replicates in totally different cells, making it difficult to study the biology of the parasite and to identify targets for the development of drugs that affect all stages. Host molecules, such as melatonin and derivatives, have been shown to play a role in the progression and regulation of the parasite’s cell cycle; In fact, when the parasite is exposed to melatonin, there is an increase in the levels of transcription of genes that code for proteins related to the ubiquitin proteasome system (UPS). This system is essential for the parasite’s survival, and drugs such as Bortezomib, MLN-273, ZL3B, epoxomycins and salinosporamides are able to eliminate the parasite by inhibiting protein degradation through the UPS. In addition, the Plasmodium UPS shows low similarity to the same human system; The identification of unique targets to be used for the development of therapeutic molecules increases the importance of UPS studies in the fight against malaria. Drugs that cause oxidative stress, such as artemisinin, show a strong synergistic effect with UPS inhibitors, increasing the possibilities of combination therapies, which are more effective with a lower concentration of drugs.

Project Details

Basic Science
Drug Resistance

Sep 2018 — Feb 2019

Brazil