**5. Parasite targets for new drugs**

**Figure 2.** Structure of terpenoids loaded in nanoformulations.

360 Leishmaniasis - Trends in Epidemiology, Diagnosis and Treatment

Parasite resistance, cost, side effects, toxicity, and other therapy issues prompt an urgent need to identify and develop new drugs and alternative targets for leishmaniasis treatment [73, 74, 10]. Metabolic pathways such as glycolytic pathway [75, 76], polyamine biosynthesis [77, 78], glyoxalase pathway [79, 80], uptake and turnover of phospholipids/sphingolipids [81, 82], microtubule biosynthesis [83, 84], and folate metabolism [85] have been targeted.

The development of drugs directed at new targets such as parasite enzymes represents another approach in the search for new antileishmanial drugs. Arginase is a recently described target for the treatment of leishmaniasis. The enzyme is localized in the glycosome, a subcellular organelle found in some trpypanosomatids such as *Leishmania*. Inhibition of the arginase pathway causes inhibits the polyamine biosynthetic pathway, resulting in antileishmanial activity [86].

Other enzyme systems investigated as potential targets for antileishmanial drug action include nitric oxide synthase, DNA topoisomerase, trypanothione redutase, superoxide dismutase enzymes, and hypoxanthine-guanine phosphoribosyltransferase [74]; heme oxygenase-1 [87]; ribose 5-phosphate isomerase B [88]; dihydroorotate dehydrogenase [89]; ornitine decarbox‐ ylases [62]; Abl family kinases and phosphoinositide 3-kinase γ [90-93]; and spermidine synthase [94, 95].

A total of 154 peptidases were detected in the *Leishmania major* genome, including serine, cysteine, aspartic, threonine, and metallopeptidases. The cysteine peptidase-specific inhibitor K11777 has shown that these peptidases are necessary for parasite growth [96]. Even though some inhibitors have been developed but failed to kill parasites, peptidases are promising targets [97-99].

Carbonic anhydrases (CAs, EC 4.2.1.1) are a new target that are starting to be studied for *Leishmania*. CAs are metalloenzymes that catalyze CO2 hydration to bicarbonate and protons, and five CA classes have been identified: α, β, γ, δ, and ζ. The reaction catalyzed by CAs is essential in the regulation of acid-base balance in organisms [100, 101]. A β-carbonic anhydrase was recently cloned and characterized from *Leishmania donovani chagasi*, and enzyme-specific inhibitors were tested against *Leishmania* [102].

The death of the parasite by inhibiting an enzyme or pathway essential for parasite survival and non-essential for the host requires the exploration of differences between these pathways or enzymes [103]. Thus, new *Leishmania* molecules should be studied and the possibility of developing rational and more effective drugs with less harmful side effects for the host investigated. Finally, new *Leishmania* chemotherapeutic targets and new approaches to the development of drugs should be considered [104, 93, 105].
