Abstract
Leishmaniasis is one of the most important neglected tropical diseases. The chemotherapy for its treatment uses very toxic compounds with a low efficacy rate. Thus, there is an urgent need to develop new chemotherapeutic agents to help countries control this devasting disease. In drug development, different approaches can be used to identify potential cellular targets that allow us to understand better the cell biology of eukaryotic cells. Several groups are dedicated to studying new molecules, searching for promising candidates against Leishmania. Different techniques have been used to characterize the cell biology, biochemistry, and molecular biology alterations induced by the treatments, trying to understand the mechanisms of action. The main goal of this chapter is to describe an overview of the literature exploring the several studies published about the chemotherapy of anti-Leishmania concerning the mechanisms of action of different classes of molecules or therapeutic alternatives.
Keywords
- chemotherapy
- drug development
- cell biology
- ergosterol
- histone deacetylases
- organometallic compounds
- therapeutic combination
- nanotechnology
1. Introduction
Leishmaniasis is a neglected tropical disease that comprises a large and complex group of infections caused by the
The ultrastructure of
The
To maintain its morphological structure,
In the Medicinal Chemistry field, several approaches have been attempted, trying to find potential cellular targets for developing anti-
2. Challenging the target: phospholipid and ergosterol biosynthesis
The first metabolically stable analogs derived from lysophosphatidylcholine were synthesized in the late 1960s. Two decades later, Eibl and Unger synthesized the first alkyl phospholipids (APLs), also called miltefosine, first administrated by an intravenous route to treat systemic tumors [10]. However, the treatment failed, and miltefosine was evaluated against topical cutaneous metastases from breast cancer [11]. In the late 1990s, miltefosine was assessed
After the evidence of the excellent anti-
Miltefosine was also evaluated in patients infected with cutaneous leishmaniasis in Colombia, Guatemala, and Brazil [19, 20]. The efficacy in this clinical manifestation was variable, depending on the species. For patients infected with
Several studies have demonstrated that the primary target of miltefosine is the cell membranes, affecting cellular processes such as signal transduction, lipid metabolism, and calcium homeostasis [21]. The selectivity for the plasma membrane is related to its chemical structure formed by a polar choline head bound to a long non-polar hydrocarbon chain, which easily inserts into the lipid bilayer, presenting detergent properties that lead to cell lysis in high concentrations [10]. In
With the success of miltefosine, several groups worldwide began to study new chemical routes to synthesize ether phospholipid derivatives in searching for novel molecules more active and selective against
Another essential metabolic route for
At least 20 metabolic steps are necessary to synthesize ergosterol, and several enzymes participate in these reaction sequences [32, 33, 34]. Furthermore, several works have shown that multiple classes of compounds targeting 24-methyl sterol biosynthesis exhibit suitable anti-trypanosomatid activities
More than 30 drugs have been studied in the last 30 years. These drugs are included in large classes of inhibitors, such as 1) Statins, which inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), also evaluated as cholesterol-lowering drugs; 2) Bisphosphonates that act in the enzyme farnesyl pyrophosphate synthase and inhibit the isoprenoid pathway, mainly used to treat hypercalcemia; 3) Quinuclidines and zaragozic acid, developed to inhibit the squalene synthase, the enzyme that catalyzes the first committed step in the sterol biosynthesis pathway. This class of drugs was developed as an alternative to statin use because they do not inhibit the synthesis of the isoprenoids. 4) Allylamines, which include the known antifungal terbinafine that inhibits the squalene epoxidase; 5) Azoles, which are essential medicines to treat many fungal diseases and inhibit the C14α-demethylase. Several azoles were developed, always trying to find new tolerate and efficacy drugs, also searching to novel molecules to solve the problems with antifungal resistance; finally, 6) Azasterols, which inhibit the enzyme Δ24,25 sterol methyltransferase absent in mammalian cells, one enzyme that catalyzes the methylation of steroid nucleus of sterols, producing 24-methyl sterols, essential for
In summary, several works have pointed to the importance of looking for the biochemical properties of each enzyme involved in the pathway and its relevance as an essential target for the parasite viability; this feature characterizes the enzyme as a promising target for the development of potential chemotherapeutic candidates for the treatment of leishmaniasis.
3. Challenging the target: histone deacetylases
Histone deacetylase (HDACs) inhibitors are a relatively new class of potential agents in treating neurodegenerative diseases, various types of cancer, and parasitic infections. HDACs have broad importance in the cellular environment. They regulate histone and non-histone proteins affecting the cell cycle, energy metabolism, and inducing cell death. Some HDAC inhibitors were already approved by the FDA (Food and Drug Administration) to treat lymphoma and myeloma, such as vorinostat, romidepsin, belinostat, and panobinostat, in combination with bortezomib and dexamethasone [40]. Given the results obtained
There are 18 histone deacetylases in humans, which can be grouped according to cell location and the molecule used as a cofactor for its enzymatic action. These HDACs are divided into 1) zinc-dependent HDACs, also called “classical” histone deacetylases; and 2) nicotinamide and adenine dinucleotide [NAD+]-dependent HDACs. The first one comprises class I (HDACs 1–3, 8), IIa (HDACs 4, 5, 7, and 9), IIb (HDACs 6 and 10), and IV (HDAC 11). While the second one, the NAD+-HDAC, belongs to class III and is also known as sirtuins (SIRT 1–7). HDACs are still poorly understood and characterized in
Unlike classical HDACs, there are several studies about NAD+-dependent HDACs in the
In
The work in [54] demonstrated that
The SIR2RP2 present in
The third sirtuin, SIR2RP3, still has few descriptions in the literature. The
A recent study with a histone deacetylase inhibitor
However, the parasite’s ability to modulate the histone deacetylases of the mammalian host to establish the infection has already been observed. For example, the upregulation of the macrophage HDAC1 was observed during infection with
Besides, HDAC inhibitors have also been used in combination therapy to treat antimony-resistant
Thus, histone deacetylase inhibitors belong to a class of compounds with potential application to develop novel molecules with anti-
4. Challenging the target: organometallic compounds
Although metals have been used in Medicine for centuries, most compounds produced by the pharmaceutical industry are still based on organic molecules. Nevertheless, new perspectives about metal-based drugs and their therapeutic potential against cancer, bacteria, virus, and even trypanosomatid infections have emerged in the last few years. In this context,
Platinum-derived metals are well known to have antitumor effects due to their ability to bind to DNA molecules. So, since tumor cells and kinetoplastid parasites present similar metabolic pathways [61], the coordination of these metals to organic compounds might be efficient in treating
In addition to platinum and its derivatives, other transition metals have been widely studied in terms of antiprotozoal activity. For example, organometallic complexes containing ruthenium(II) and anti-inflammatories were evaluated active against
Among transition metals, the essential ones, such as zinc and copper, are present in cell structures and involved in many cellular processes, becoming indispensable for host–parasite interactions. Zinc regulates gene transcription processes and cell signaling, while copper is also a critical enzymatic cofactor for organ functioning and multiple metabolic processes [66]. Therefore, the coordination of organic molecules to essential metals regarding new antiprotozoal treatments might increase the drug uptake and contribute to the parasite’s elimination. The zinc(II)-dipicolylamine (ZnDPA) coordination complexes were active against
Metals have also been combined with ergosterol biosynthesis inhibitors, including the azoles family of drugs, which are used to treat fungal infections and present activity against protozoan parasites. For example, a recent study from our group revealed the potent effect of the combination of itraconazole (ITZ) with zinc (Zn) against
Despite Medicine’s advances in the past decades, information about organometallic drugs is still lacking. More profound studies must be done to understand the role of metals in host–parasite interactions, thereby better comprising the mechanisms of organometallics drugs against the parasites and mammalian host cells. Nevertheless, the literature available indicates that organometallics are a promising class of drugs for treating leishmaniasis.
5. Therapeutic combination: what do we know?
There are many strategies to treat leishmaniasis; however, several studies have shown the numerous advantages of therapeutic combination, like observing for other diseases. For example, combining drugs from different chemical classes could reduce the total drug doses or treatment duration. These aspects are important to minimize toxic side effects, submission at treatment, less load on the public health system and reduce cases of drug resistance. Also, the therapeutic combination could improve treatment efficacy for refractory or complicated cases, such as in patients coinfected with HIV. A successful study conducted by the Drugs for Neglected Diseases initiative (DNDi), in partnership with Médicins Sans Frontières (MSF) and other institutions, pointed to evidence of the high efficacy of the combination therapy to treat patients with visceral leishmaniasis (VL) in coinfection with HIV [71]. Although the current WHO guidelines recommend the treatment of HIV/VL coinfection with liposomal amphotericin B (AmBisome®), this work strongly supports a change in the treatment recommendations, from AmBisome monotherapy to combination therapy as the first-line treatment. Moreover, they suggest the combination with miltefosine once this combination therapy has a good safety profile and is highly efficacious [71].
Nowadays, combination therapy is an efficient tool to treat many microbial infections such as AIDS, tuberculosis, malaria, and several other diseases. Recent works have shown that combination therapy for leishmaniasis has progressively been recommended to increase treatment tolerance and efficacy, reduce cost and treatment duration, and limit the growth of drug resistance [72, 73, 74, 75]. For the treatment of leishmaniasis, WHO has recommended combination therapy based on many studies showing the efficacy of this therapeutic tool; the combinations include novel synthesized drugs, nanoparticles developed for drug delivery, repositioned drugs, old medicines, and immunomodulatory agents [76, 77, 78, 79]. Indeed, several studies have reported the superior efficacies of combination therapies against leishmaniasis. Some of them demonstrated the synergic effects of combinations between amphotericin B with other available medicines, such as meglumine antimoniate, miltefosine, paromomycin, or azithromycin [80, 81, 82].
Analysis of drug interactions aimed to show if the interaction between them is classified as synergistic, antagonistic, or indifferent.
Combination therapy is a promising strategy to treat several diseases. Therefore, it is urgent to investigate synergistic and other drug combinations to increase novel probabilities of therapeutic protocols to treat leishmaniasis. The discovery and the analysis of drug combinations can be facilitated by the collective use of different approaches and methods. Drug combinations have proved to be a successful strategy to shorten the course of therapy and reduce toxicity through lower dosage administration; these strategies should reduce the appearance of new resistant parasites. Thus, recent proposals of combinations have been suggested as state-of-the-art for the treatment of leishmaniasis. In the short run, combination therapy is an interesting way to improve the treatment for leishmaniasis.
6. Where are we going? Nanotechnology
Recent advances in Nanotechnology have had a profound impact on health sciences, especially Medicine, because of the development of different nanomaterials designed as intracellular carriers to deliver drugs and genes. The development and use of nanocarriers have also been established in the field of Pharmaceutical Sciences by enabling the encapsulation of drugs creating stable and controlled environments, and improving the biocompatibility of these drugs in various biological systems. These nanocarriers were developed to improve the solubility of poorly soluble drugs, control or maintain their release, and protect them from degradation. These characteristics increase drug bioavailability, reduce systemic side effects, and increase drug specificity for biological targets. For these reasons, Nanotechnology is a new field that allows the construction of versatile diagnostic and therapeutic platforms using nanocarriers as molecular machinery for different clinical applications.
The development of nanocarriers began in the 1960s to always seek to improve biocompatibility and reduce the toxicity of nanomaterials. The second generation of nanocarriers was developed around the 1980s and sought to improve the surface of these materials by increasing their stability, stealth, and targeting ability. The third generation of nanocarrier introduced the idea of intelligent nanomedication to enhance the targeting mechanisms and theranostic capabilities of these nanomaterials [89]. The word
Initially, the nanomaterials are divided into two classes: inorganic and organic. However, they are divided into three subgroups, according to some of their characteristics. The first would concentrate single-chain polymer-drug conjugates, polymeric colloids prepared by techniques such as emulsion polymerization, cross-linked nanogel matrices, dendrimers, and carbon nanotubes, where the nanocarrier is a single synthetic molecule with covalent bonds and a relatively large molar mass. The second subgroup of nanocarriers would comprise self-assembly of smaller molecules such as 1) liposomes and polyplexes, the most studied members of this group of nanoparticles; 2) polymersomes and other sets of block copolymers; 3) colloidosomal aggregates of latex particles and sets of proteins or peptides. In this case, the dynamic nature of these types of systems depends on intermolecular forces and biological conditions. Finally, the last subgroup of nanocarriers would include complexes based on fullerenes, silica, colloidal gold, gold nanoshells, quantum dots, and superparamagnetic particles.
Another critical point in developing nanocarriers is the synthesis, which can be rationally divided into two fundamental stages: nucleation and growth. Understanding and manipulating these two steps have created new possibilities allowing researchers to easily control the synthesis of nanoparticles in terms of size, morphology, and monodispersity. The choice of the synthesis route provides a characteristic set of advantages and disadvantages in nanomaterial production.
In
The success achieved by the liposomal formulation of amphotericin B is related to its properties as a nanocarrier system, which has numerous advantages. However, despite these advantages, this system has some disadvantages, including its high cost, limiting its use [94]. Thus, the development of new, cheaper, and more efficient nanoformulations is necessary. Furthermore, different nanocarriers have been developed in recent decades, searching for new therapeutic alternatives to treat leishmaniasis, including nanoparticles based on liposomal, lipid, polymeric, and metallic nanomaterials [8, 95, 96, 97, 98]. Therefore, choosing the correct nanocarriers is crucial to define properties and characteristics for this proposed new therapeutic approach. Thereby, this enormous diversity of available nanoparticles makes the development of nanocarriers for the treatment of leishmaniasis very promising since each of these carrier systems has advantages and limitations over each other [8].
Some nanoparticles have been generating significant repercussions for presenting theranostic properties, thus allowing them to be used simultaneously for diagnosis and therapy. Superparamagnetic iron oxide nanoparticles (SPIONs) are one example of this type of nanomaterials. SPIONs have excellent biocompatibility, degradability in moderate acid conditions, magnetic properties, and the ability to generate heat when subjected to an alternating current magnetic field [99, 100]. In addition, this type of nanomaterial still has a large surface area presenting great chemical diversity, which can increase the efficacy of the treatment. Finally, these nanomaterials can also be conjugated to specific molecules to facilitate selective and efficient drug delivery to a diseased tissue or organ [101]. The application of this type of nanomaterial for the treatment of leishmaniasis has been studied by different groups and has shown promising results over the past few years (Figure 6) [102, 103, 104, 105].
In summary, Nanotechnology and the use of nanoparticles inaugurated a new field in health science called Nanomedicine, one of the most promising branches of contemporary Medicine. Thus, the development of new nanomaterials to treat leishmaniasis significantly increases the possibility of finding novel therapeutic alternatives, mainly considering the great diversity of clinical manifestations. An excellent example of this is the use of nanoparticles to develop a topical treatment that can revolutionize the treatment of cutaneous leishmaniasis.
7. Conclusions and perspectives
The treatment of infectious diseases depends on a better understanding of Cell Biology, mainly for parasites that are intracellular obligate eukaryotes, such as
Acknowledgments
We acknowledge the Brazilian funding agencies Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento e Pesquisa (CNPq), and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) for financial support.
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