scholarly journals The Sphingolipid Biosynthetic Pathway Is a Potential Target for Chemotherapy against Chagas Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Carolina Macedo Koeller ◽  
Norton Heise
Keyword(s):  
Chagas Disease ◽  
Drug Targets ◽  
Biosynthetic Pathway ◽  
Protozoan Parasite ◽  
Surface Expression ◽  
Sequence Information ◽  
Insect Vector ◽  
Biosynthetic Pathways ◽  
Genome Sequence Information ◽  
Intracellular Stage

The protozoan parasite Trypanosoma cruzi is the causative agent of human Chagas disease, for which there currently is no cure. The life cycle of T. cruzi is complex, including an extracellular phase in the triatomine insect vector and an obligatory intracellular stage inside the vertebrate host. These phases depend on a variety of surface glycosylphosphatidylinositol-(GPI-) anchored glycoconjugates that are synthesized by the parasite. Therefore, the surface expression of GPI-anchored components and the biosynthetic pathways of GPI anchors are attractive targets for new therapies for Chagas disease. We identified new drug targets for chemotherapy by taking the available genome sequence information and searching for differences in the sphingolipid biosynthetic pathways (SBPs) of mammals and T. cruzi. In this paper, we discuss the major steps of the SBP in mammals, yeast and T. cruzi, focusing on the IPC synthase and ceramide remodeling of T. cruzi as potential therapeutic targets for Chagas disease.

scholarly journals Identification of Inhibitors to Trypanosoma cruzi Sirtuins Based on Compounds Developed to Human Enzymes

2020 ◽  
Vol 21 (10) ◽  
pp. 3659
Author(s):  
Tanira Matutino Bastos ◽  
Milena Botelho Pereira Soares ◽  
Caio Haddad Franco ◽  
Laura Alcântara ◽  
Lorenzo Antonini ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Mammalian Cells ◽  
Drug Target ◽  
Drug Targets ◽  
Synergistic Effects ◽  
Protozoan Parasite ◽  
Disease Treatment ◽  
Specific Parasite ◽  
Specific Inhibitors

Chagas disease is an illness caused by the protozoan parasite Trypanosoma cruzi, affecting more than 7 million people in the world. Benznidazole and nifurtimox are the only drugs available for treatment and in addition to causing several side effects, are only satisfactory in the acute phase of the disease. Sirtuins are NAD+-dependent deacetylases involved in several biological processes, which have become drug target candidates in various disease settings. T. cruzi presents two sirtuins, one cytosolic (TcSir2rp1) and the latter mitochondrial (TcSir2rp3). Here, we characterized the effects of human sirtuin inhibitors against T. cruzi sirtuins as an initial approach to develop specific parasite inhibitors. We found that, of 33 compounds tested, two inhibited TcSir2rp1 (15 and 17), while other five inhibited TcSir2rp3 (8, 12, 13, 30, and 32), indicating that specific inhibitors can be devised for each one of the enzymes. Furthermore, all inhibiting compounds prevented parasite proliferation in cultured mammalian cells. When combining the most effective inhibitors with benznidazole at least two compounds, 17 and 32, demonstrated synergistic effects. Altogether, these results support the importance of exploring T. cruzi sirtuins as drug targets and provide key elements to develop specific inhibitors for these enzymes as potential targets for Chagas disease treatment.

Isoprenoid biosynthetic pathways as anti-infective drug targets

2005 ◽  
Vol 33 (4) ◽  
pp. 785-791 ◽  
Author(s):  
F. Rohdich ◽  
A. Bacher ◽  
W. Eisenreich
Keyword(s):  
Helicobacter Pylori ◽  
Plasmodium Falciparum ◽  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Biosynthetic Pathway ◽  
Mevalonate Pathway ◽  
Biosynthetic Pathways ◽  
Isopentenyl Diphosphate ◽  
Human Pathogens ◽  
Dimethylallyl Diphosphate

IPP (isopentenyl diphosphate) and DMAPP (dimethylallyl diphosphate) serve as the universal precursors for the biosynthesis of isoprenoids. Besides the well-known mevalonate pathway, the existence of a second biosynthetic pathway conducive to IPP and DMAPP formation through 1-deoxy-D-xylulose 5-phosphate and 2C-methyl-D-erythritol 4-phosphate was discovered approx. 10 years ago in plants and certain eubacteria. It is now known that this pathway is widely distributed in the bacterial kingdom including major human pathogens, such as Mycobacterium tuberculosis and Helicobacter pylori. The pathway is also essential in the malaria vector Plasmodium falciparum. During the last few years, the genes, enzymes, intermediates and mechanisms of the biosynthetic route have been elucidated by a combination of comparative genomics, enzymology, advanced NMR technology and crystallography. The results provide the basis for the development of novel anti-infective drugs.

scholarly journals Genomewide Analysis of Mode of Action of the S-Adenosylmethionine Analogue Sinefungin in Leishmania infantum

mSystems ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Arijit Bhattacharya ◽  
Mansi Sharma ◽  
Charles Packianathan ◽  
Barry P. Rosen ◽  
Philippe Leprohon ◽  
...  
Keyword(s):  
Drug Targets ◽  
Protozoan Parasite ◽  
Cell Types ◽  
Biosynthetic Pathways ◽  
Potential Drug ◽  
Pathogenic Parasite ◽  
Potential Drug Targets ◽  
Chemotherapeutic Interventions

The two main cellular metabolic one-carbon donors are reduced folates and S-adenosylmethionine, whose biosynthetic pathways have proven highly effective in chemotherapeutic interventions in various cell types. Sinefungin, a nucleoside analogue of S-adenosylmethionine, was shown to have potent activity against the protozoan parasite Leishmania. Here, we studied resistance to sinefungin using whole-genome approaches as a way to further our understanding of the role of S-adenosylmethionine in this parasite and to reveal novel potential drug targets. These approaches allowed the characterization of novel features related to S-adenosylmethionine function in Leishmania which could further help in the development of sinefungin-like compounds against this pathogenic parasite.

Acanthamoeba Keratitis: Current Status and Urgent Research Priorities

2019 ◽  
Vol 26 (30) ◽  
pp. 5711-5726 ◽  
Author(s):  
Naveed Ahmed Khan ◽  
Ayaz Anwar ◽  
Ruqaiyyah Siddiqui
Keyword(s):  
Rational Design ◽  
Research Priorities ◽  
Acanthamoeba Keratitis ◽  
Current Treatment ◽  
Research Literature ◽  
Current Status ◽  
Bibliographic Databases ◽  
Sequence Information ◽  
Therapeutic Measures ◽  
Genome Sequence Information

Background:First discovered in the early 1970s, Acanthamoeba keratitis has remained a major eye infection and presents a significant threat to the public health, especially in developing countries. The aim is to present a timely review of our current understanding of the advances made in this field in a comprehensible manner and includes novel concepts and provides clear directions for immediate research priorities.Methods:We undertook a search of bibliographic databases for peer-reviewed research literature and also summarized our published results in this field.Results:The present review focuses on novel diagnostic and therapeutic strategies in details which can provide access to management and treatment of Acanthamoeba keratitis. This coupled with the recently available genome sequence information together with high throughput genomics technology and innovative approaches should stimulate interest in the rational design of preventative and therapeutic measures. Current treatment of Acanthamoeba keratitis is problematic and often leads to infection recurrence. Better understanding of diagnosis, pathogenesis, pathophysiology and therapeutic regimens, would lead to novel strategies in treatment and prophylaxis.

Major Kinds of Drug Targets in Chagas Disease or American Trypanosomiasis

2019 ◽  
Vol 20 (11) ◽  
pp. 1203-1216 ◽  
Author(s):  
Vilma G. Duschak
Keyword(s):  
Chagas Disease ◽  
Latin American ◽  
Drug Targets ◽  
Defense Mechanisms ◽  
Cysteine Proteinase ◽  
Parasitic Infection ◽  
Etiologic Agent ◽  
World Health ◽  
American Trypanosomiasis ◽  
Group I

American Trypanosomiasis, a parasitic infection commonly named Chagas disease, affects millions of people all over Latin American countries. Presently, the World Health Organization (WHO) predicts that the number of international infected individuals extends to 7 to 8 million, assuming that more than 10,000 deaths occur annually. The transmission of the etiologic agent, Trypanosoma cruzi, through people migrating to non-endemic world nations makes it an emergent disease. The best promising targets for trypanocidal drugs may be classified into three main groups: Group I includes the main molecular targets that are considered among specific enzymes involved in the essential processes for parasite survival, principally Cruzipain, the major antigenic parasite cysteine proteinase. Group II involves biological pathways and their key specific enzymes, such as Sterol biosynthesis pathway, among others, specific antioxidant defense mechanisms, and bioenergetics ones. Group III includes the atypical organelles /structures present in the parasite relevant clinical forms, which are absent or considerably different from those present in mammals and biological processes related to them. These can be considered potential targets to develop drugs with extra effectiveness and fewer secondary effects than the currently used therapeutics. An improved distinction between the host and the parasite targets will help fight against this neglected disease.

scholarly journals Metabolic reprogramming during the Trypanosoma brucei life cycle

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 683 ◽  
Author(s):  
Terry K. Smith ◽  
Frédéric Bringaud ◽  
Derek P. Nolan ◽  
Luisa M. Figueiredo
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
Model Organism ◽  
Protozoan Parasite ◽  
Tsetse Fly ◽  
Metabolic Reprogramming ◽  
Mammalian Host ◽  
Insect Vector ◽  
Environmental Signals ◽  
Cellular Metabolic Activity

Cellular metabolic activity is a highly complex, dynamic, regulated process that is influenced by numerous factors, including extracellular environmental signals, nutrient availability and the physiological and developmental status of the cell. The causative agent of sleeping sickness, Trypanosoma brucei, is an exclusively extracellular protozoan parasite that encounters very different extracellular environments during its life cycle within the mammalian host and tsetse fly insect vector. In order to meet these challenges, there are significant alterations in the major energetic and metabolic pathways of these highly adaptable parasites. This review highlights some of these metabolic changes in this early divergent eukaryotic model organism.

Temperature, Mitochondria, and Reye's Syndrome

PEDIATRICS ◽  
1983 ◽  
Vol 71 (6) ◽  
pp. 985-985
Author(s):  
RIF S. EL-MALLAKH
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Protozoan Parasite ◽  
Mitochondrial Enzyme ◽  
Reye's Syndrome ◽  
Electron Microscopic ◽  
Microscopic Studies ◽  
Mitochondrial Defect ◽  
Intracellular Protozoan Parasite

To the Editor.— Mitochondrial failure, manifest by changes in mitochondrial enzyme activity1-3 and morphology,4-5 is central to Reye's syndrome (RS).6 Although it has been variously hypothesized that the mitochondrial changes are secondary to an exogenous toxin,7-12 or an intrinsic mitochondrial defect,6 the actual cause remains obscure. Electron microscopic studies have shown sweelling and loss of cristate in mitochondria of patients with RS. It is interesting that very similar changes occur in Trypanosoma cruzi.13-16 T cruzi is an extracellular/intracellular protozoan parasite which causes Chagas' disease.17

scholarly journals Evolutionary relationships of completely sequenced Clostridia species and close relatives

2015 ◽  
Vol 65 (Pt_11) ◽  
pp. 4276-4283 ◽  
Author(s):  
Takashi Kunisawa
Keyword(s):  
Maximum Likelihood ◽  
Phylogenetic Trees ◽  
Gene Arrangement ◽  
Evolutionary Relationships ◽  
Rrna Gene ◽  
Sequence Information ◽  
Bayesian Tree ◽  
Maximum Likelihood Methods ◽  
Genome Sequence Information ◽  
Close Relatives

The class Clostridia in the phylum Firmicutes includes a very heterogeneous assemblage of bacteria. Their evolutionary relationships are not well established; revisions of their phylogenetic placements based on comparative studies of 16S rRNA gene sequences are in progress as genome sequence information accumulates. In this work, phylogenetic trees were reconstructed based on 21 concatenated ribosomal protein sequences using Bayesian and maximum-likelihood methods. Both trees consistently indicate that the Halanaerobiales is a deeply branching order among the class Clostridia. The rest of the Clostridia species are grouped into 10 monophyletic clusters, most of which are comprised of two or three orders and families according to the current Clostridial taxonomy. The maximum-likelihood tree placed Coprothermobacter proteolyticus and Thermodesulfobium narugense in the class Clostridia in accordance with the current taxonomy, in which these two bacteria are assigned to the family Thermodesulfobiaceae. However, the Bayesian tree placed these two bacteria at the boundary between the Firmicutes and Actinobacteria. A gene arrangement that is present uniquely in the Firmicutes species was identified. Both Coprothermobacter proteolyticus and Thermodesulfobium narugense do not have this arrangement characteristic of the Firmicutes. On the basis of the Bayesian tree and gene arrangement comparison, it is suggested that Coprothermobacter proteolyticus and Thermodesulfobium narugense should be placed outside the phylum Firmicutes.

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