Search

Background: As a result of the paucity of treatment, Leishmaniasis continues to provoke about 60,000 deaths every year worldwide. New molecules are needed, and drug discovery research is oriented toward targeting proteins crucial for parasite survival. Among them, trypanothione reductase (TR) is of remarkable interest owing to its vital role in Leishmania species protozoan parasite life. Our previously identified compound 1 is a novel chemotype endowed with a unique mode of TR inhibition thanks to its binding to a formerly unknown but druggable site at the entrance of the NADPH binding cavity, absent in human glutathione reductase (hGR). Methods: We designed and synthesized new 3-amino-1-arylpropan-1-one derivatives structurally related to compound 1 and evaluated their potential inhibition activity on TR from Leishmania infantum (LiTR). Cluster docking was performed to assess the binding poses of the compounds. Results: The newly synthesized compounds were screened at a concentration of 100 μM in in vitro assays and all of them proved to be active with residual activity percentages lower than 75%. Conclusions: Compounds 2a and 2b were the most potent inhibitors found, suggesting that an additional aromatic ring might be promising for enzymatic inhibition. Further structure–activity relationships are needed to optimize our compounds activity.

The protozoans Leishmania and Trypanosoma, belonging to the same Trypanosomatidae family, are the causative agents of Leishmaniasis, Chagas disease, and human African trypanosomiasis. Overall, these infections affect millions of people worldwide, posing a serious health issue as well as socio-economical concern. Current treatments are inadequate, mainly due to poor efficacy, toxicity, and emerging resistance; therefore, there is an urgent need for new drugs. Among several molecular targets proposed, trypanothione reductase (TR) is of particular interest for its critical role in controlling the parasite’s redox homeostasis and several classes of active compounds that inhibit TR have been proposed so far. This review provides a comprehensive overview of TR’s structural characterization. In particular, we discuss all the structural features of TR relevant for drug discovery, with a focus on the recent advances made in the understanding of inhibitor binding. The reported cases show how, on the basis of the detailed structural information provided by the crystallographic analysis, it is possible to rationally modify molecular scaffolds to improve their properties.

Sorcin is a penta-EF hand calcium binding protein, which participates in the regulation of calcium homeostasis in cells. Sorcin regulates calcium channels and exchangers located at the plasma membrane and at the endo/sarcoplasmic reticulum (ER/SR), and allows high levels of calcium in the ER to be maintained, preventing ER stress and possibly, the unfolded protein response. Sorcin is highly expressed in the heart and in the brain, and overexpressed in many cancer cells. Sorcin gene is in the same amplicon as other genes involved in the resistance to chemotherapeutics in cancer cells (multi-drug resistance, MDR) such as ABCB4 and ABCB1; its overexpression results in increased drug resistance to a number of chemotherapeutic agents, and inhibition of sorcin expression by sorcin-targeting RNA interference leads to reversal of drug resistance. Sorcin is increasingly considered a useful marker of MDR and may represent a therapeutic target for reversing tumor multidrug resistance.