scholarly journals The ubiquinone synthesis pathway is a promising drug target for Chagas disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0243855
Author(s):  
Takeshi Nara ◽  
Yukari Nakagawa ◽  
Keiko Tsuganezawa ◽  
Hitomi Yuki ◽  
Katsuhiko Sekimata ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Latin American ◽  
Drug Target ◽  
Culture Medium ◽  
Protozoan Parasite ◽  
Redox Balance ◽  
New Drugs ◽  
Key Enzyme ◽  
2D And 3D ◽  
Similarity Searches

Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi). It was originally a Latin American endemic health problem, but now is expanding worldwide as a result of increasing migration. The currently available drugs for Chagas disease, benznidazole and nifurtimox, provoke severe adverse effects, and thus the development of new drugs is urgently required. Ubiquinone (UQ) is essential for respiratory chain and redox balance in trypanosomatid protozoans, therefore we aimed to provide evidence that inhibitors of the UQ biosynthesis have trypanocidal activities. In this study, inhibitors of the human COQ7, a key enzyme of the UQ synthesis, were tested for their trypanocidal activities because they were expected to cross-react and inhibit trypanosomal COQ7 due to their genetic homology. We show the trypanocidal activity of a newly found human COQ7 inhibitor, an oxazinoquinoline derivative. The structurally similar compounds were selected from the commercially available compounds by 2D and 3D ligand-based similarity searches. Among 38 compounds selected, 12 compounds with the oxazinoquinoline structure inhibited significantly the growth of epimastigotes of T. cruzi. The most effective 3 compounds also showed the significant antitrypanosomal activity against the mammalian stage of T. cruzi at lower concentrations than benznidazole, a commonly used drug today. We found that epimastigotes treated with the inhibitor contained reduced levels of UQ9. Further, the growth of epimastigotes treated with the inhibitors was partially rescued by UQ10 supplementation to the culture medium. These results suggest that the antitrypanosomal mechanism of the oxazinoquinoline derivatives results from inhibition of the trypanosomal UQ synthesis leading to a shortage of the UQ pool. Our data indicate that the UQ synthesis pathway of T. cruzi is a promising drug target for Chagas disease.

scholarly journals Imidazole Derivatives as Promising Agents for the Treatment of Chagas Disease

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Julianna Siciliano de Araújo ◽  
Alfonso García-Rubia ◽  
Victor Sebastián-Pérez ◽  
Titilola D. Kalejaiye ◽  
Patrícia Bernardino da Silva ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Latin American ◽  
Protozoan Parasite ◽  
Aqueous Solubility ◽  
Content Type ◽  
Cellular Effects ◽  
Transmission Electron ◽  
Phenotypic Screen ◽  
Current Therapies ◽  
Potential Inhibitors

ABSTRACT More than 100 years after being first described, Chagas disease remains endemic in 21 Latin American countries and has spread to other continents. Indeed, this disease, which is caused by the protozoan parasite Trypanosoma cruzi, is no longer just a problem for the American continents but has become a global health threat. Current therapies, i.e., nifurtimox and benznidazole (Bz), are far from being adequate, due to their undesirable effects and their lack of efficacy in the chronic phases of the disease. In this work, we present an in-depth phenotypic evaluation in T. cruzi of a new class of imidazole compounds, which were discovered in a previous phenotypic screen against different trypanosomatids and were designed as potential inhibitors of cAMP phosphodiesterases (PDEs). The confirmation of several activities similar or superior to that of Bz prompted a synthesis program of hit optimization and extended structure-activity relationship aimed at improving drug-like properties such as aqueous solubility, which resulted in additional hits with 50% inhibitory concentration (IC50) values similar to that of Bz. The cellular effects of one representative hit, compound 9, on bloodstream trypomastigotes were further investigated. Transmission electron microscopy revealed cellular changes, after just 2 h of incubation with the IC50 concentration, that were consistent with induced autophagy and osmotic stress, mechanisms previously linked to cAMP signaling. Compound 9 induced highly significant increases in both cellular and medium cAMP levels, confirming that inhibition of T. cruzi PDE(s) is part of its mechanism of action. The potent and selective activity of this imidazole-based PDE inhibitor class against T. cruzi constitutes a successful repurposing of research into inhibitors of mammalian PDEs.

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.

scholarly journals Quinuclidine Derivatives as Potential Antiparasitics

2007 ◽  
Vol 51 (11) ◽  
pp. 4049-4061 ◽  
Author(s):  
Simon B. Cammerer ◽  
Carmen Jimenez ◽  
Simon Jones ◽  
Ludovic Gros ◽  
Silvia Orenes Lorente ◽  
...  
Keyword(s):  
Drug Target ◽  
Human African Trypanosomiasis ◽  
Leishmania Major ◽  
Sterol Biosynthesis ◽  
New Drugs ◽  
Causative Organism ◽  
Design And Synthesis ◽  
Human Enzyme ◽  
Key Enzyme ◽  
Potential Inhibitors

ABSTRACT There is an urgent need for the development of new drugs for the treatment of tropical parasitic diseases such as Chagas' disease and leishmaniasis. One potential drug target in the organisms that cause these diseases is sterol biosynthesis. This paper describes the design and synthesis of quinuclidine derivatives as potential inhibitors of a key enzyme in sterol biosynthesis, squalene synthase (SQS). A number of compounds that were inhibitors of the recombinant Leishmania major SQS at submicromolar concentrations were discovered. Some of these compounds were also selective for the parasite enzyme rather than the homologous human enzyme. The compounds inhibited the growth of and sterol biosynthesis in Leishmania parasites. In addition, we identified other quinuclidine derivatives that inhibit the growth of Trypanosoma brucei (the causative organism of human African trypanosomiasis) and Plasmodium falciparum (a causative agent of malaria), but through an unknown mode(s) of action.

scholarly journals Lipophilic Antifolate Trimetrexate Is a Potent Inhibitor of Trypanosoma cruzi: Prospect for Chemotherapy of Chagas' Disease

2005 ◽  
Vol 49 (8) ◽  
pp. 3234-3238 ◽  
Author(s):  
Olga Senkovich ◽  
Vandanajay Bhatia ◽  
Nisha Garg ◽  
Debasish Chattopadhyay
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Dihydrofolate Reductase ◽  
Drug Target ◽  
Potent Inhibitor ◽  
Pneumocystis Carinii ◽  
Lethal Dose ◽  
Public Health Problem ◽  
Protozoan Parasite ◽  
Track Record

ABSTRACT Trypanosoma cruzi, a protozoan parasite, is the causative agent for Chagas' disease, which poses serious public health problem in Latin America. The two drugs available for the treatment of this disease are effective only against recent infections and are toxic. Dihydrofolate reductase (DHFR) has a proven track record as a drug target. The lipophilic antifolate trimetrexate (TMQ), which is an FDA-approved drug for the treatment of Pneumocystis carinii infection in AIDS patients, is a potent inhibitor of T. cruzi DHFR activity, with an inhibitory constant of 6.6 nM. The compound is also highly effective in killing T. cruzi parasites. The 50 and 90% lethal dose values against the trypomastigote are 19 and 36 nM, and the corresponding values for the amastigote form are 26 and 72 nM, respectively. However, as TMQ is also a good inhibitor of human DHFR, further improvement of the selectivity of this drug would be preferable. Identification of a novel antifolate selective against T. cruzi would open up new therapeutic avenues for treatment of Chagas' disease.

scholarly journals Biochemical Studies of Mitochondrial Malate: Quinone Oxidoreductase from Toxoplasma gondii

2021 ◽  
Vol 22 (15) ◽  
pp. 7830
Author(s):  
Rajib Acharjee ◽  
Keith K. Talaam ◽  
Endah D. Hartuti ◽  
Yuichi Matsuo ◽  
Takaya Sakura ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Drug Target ◽  
Tricarboxylic Acid Cycle ◽  
Expression System ◽  
Protozoan Parasite ◽  
New Drugs ◽  
Quinone Oxidoreductase ◽  
Steady State Kinetics ◽  
Transport Chain ◽  
Effective Drugs

Toxoplasma gondii is a protozoan parasite that causes toxoplasmosis and infects almost one-third of the global human population. A lack of effective drugs and vaccines and the emergence of drug resistant parasites highlight the need for the development of new drugs. The mitochondrial electron transport chain (ETC) is an essential pathway for energy metabolism and the survival of T. gondii. In apicomplexan parasites, malate:quinone oxidoreductase (MQO) is a monotopic membrane protein belonging to the ETC and a key member of the tricarboxylic acid cycle, and has recently been suggested to play a role in the fumarate cycle, which is required for the cytosolic purine salvage pathway. In T. gondii, a putative MQO (TgMQO) is expressed in tachyzoite and bradyzoite stages and is considered to be a potential drug target since its orthologue is not conserved in mammalian hosts. As a first step towards the evaluation of TgMQO as a drug target candidate, in this study, we developed a new expression system for TgMQO in FN102(DE3)TAO, a strain deficient in respiratory cytochromes and dependent on an alternative oxidase. This system allowed, for the first time, the expression and purification of a mitochondrial MQO family enzyme, which was used for steady-state kinetics and substrate specificity analyses. Ferulenol, the only known MQO inhibitor, also inhibited TgMQO at IC50 of 0.822 μM, and displayed different inhibition kinetics compared to Plasmodium falciparum MQO. Furthermore, our analysis indicated the presence of a third binding site for ferulenol that is distinct from the ubiquinone and malate sites.

Effect of capsaicin on the protozoan parasite Trypanosoma cruzi

2020 ◽  
Vol 367 (23) ◽  
Author(s):  
Edward A Valera-Vera ◽  
Chantal Reigada ◽  
Melisa Sayé ◽  
Fabio A Digirolamo ◽  
Facundo Galceran ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Stress Responses ◽  
Mammalian Cells ◽  
Arginine Kinase ◽  
Chronic Phase ◽  
Protozoan Parasite ◽  
New Drugs ◽  
Cellular Stress Responses ◽  
The Difference

ABSTRACT Trypanosoma cruzi is the causative agent of Chagas disease. There are only two approved treatments, both of them unsuitable for the chronic phase, therefore the development of new drugs is a priority. Trypanosoma cruzi arginine kinase (TcAK) is a promising drug target since it is absent in humans and it is involved in cellular stress responses. In a previous study, possible TcAK inhibitors were identified through computer simulations resulting the best compounds capsaicin and cyanidin derivatives. Here, we evaluate the effect of capsaicin on TcAK activity and its trypanocidal effect. Although capsaicin produced a weak enzyme inhibition, it had a strong trypanocidal effect on epimastigotes and trypomastigotes (IC50 = 6.26 µM and 0.26 µM, respectively) being 20-fold more active on trypomastigotes than mammalian cells. Capsaicin was also active on the intracellular cycle reducing by half the burst of trypomastigotes at approximately 2 µM. Considering the difference between the concentrations at which parasite death and TcAK inhibition occur, other possible targets were predicted. Capsaicin is a selective trypanocidal agent active in nanomolar concentrations, with an IC50 57-fold lower than benznidazole, the drug currently used for treating Chagas disease.

scholarly journals Experimental Vaccines against Chagas Disease: A Journey through History

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Olivia Rodríguez-Morales ◽  
Víctor Monteón-Padilla ◽  
Silvia C. Carrillo-Sánchez ◽  
Martha Rios-Castro ◽  
Mariana Martínez-Cruz ◽  
...  
Keyword(s):  
Primary Prevention ◽  
Chagas Disease ◽  
Latin American ◽  
Protozoan Parasite ◽  
Immune Protection ◽  
Transmission Control ◽  
American Trypanosomiasis ◽  
Control Programs ◽  
Primary Prevention Strategy ◽  
Latin American Countries

Chagas disease, or American trypanosomiasis, which is caused by the protozoan parasiteTrypanosoma cruzi, is primarily a vector disease endemic in 21 Latin American countries, including Mexico. Although many vector control programs have been implemented,T. cruzihas not been eradicated. The development of an anti-T. cruzivaccine for prophylactic and therapeutic purposes may significantly contribute to the transmission control of Chagas disease. Immune protection against experimental infection withT. cruzihas been studied since the second decade of the last century, and many types of immunogens have been used subsequently, such as killed or attenuated parasites and new DNA vaccines. This primary prevention strategy appears feasible, effective, safe, and inexpensive, although problems remain. The objective of this review is to summarize the research efforts about the development of vaccines against Chagas disease worldwide. A thorough literature review was conducted by searching PubMed with the terms “Chagas disease” and “American trypanosomiasis” together with “vaccines” or “immunization”. In addition, reports and journals not cited in PubMed were identified. Publications in English, Spanish, and Portuguese were reviewed.

scholarly journals Novel Saccharomyces cerevisiae Screen Identifies WR99210 Analogues That Inhibit Mycobacterium tuberculosis Dihydrofolate Reductase

2002 ◽  
Vol 46 (11) ◽  
pp. 3362-3369 ◽  
Author(s):  
A'Lissa B. Gerum ◽  
Jonathan E. Ulmer ◽  
David P. Jacobus ◽  
Norman P. Jensen ◽  
David R. Sherman ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mycobacterium Tuberculosis ◽  
Dihydrofolate Reductase ◽  
Drug Target ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Treatment Regimens ◽  
Key Enzyme ◽  
Level 3

ABSTRACT The ongoing selection of multidrug-resistant strains of Mycobacterium tuberculosis has markedly reduced the effectiveness of the standard treatment regimens. Thus, there is an urgent need for new drugs that are potent inhibitors of M. tuberculosis, that exhibit favorable resistance profiles, and that are well tolerated by patients. One promising drug target for treatment of mycobacterial infections is dihydrofolate reductase (DHFR; EC 1.5.1.3), a key enzyme in folate utilization. DHFR is an important drug target in many pathogens, but it has not been exploited in the search for drugs effective against M. tuberculosis. The triazine DHFR inhibitor WR99210 has been shown to be effective against other mycobacteria. We show here that WR99210 is also a potent inhibitor of M. tuberculosis and Mycobacterium bovis BCG growth in vitro and that resistance to WR99210 occurred less frequently than resistance to either rifampin or isoniazid. Screening of drugs with M. tuberculosis cultures is slow and requires biosafety level 3 facilities and procedures. We have developed an alternative strategy: initial screening in an engineered strain of the budding yeast Saccharomyces cerevisiae that is dependent on the M. tuberculosis DHFR for its growth. Using this system, we have screened 19 compounds related to WR99210 and found that 7 of these related compounds are also potent inhibitors of the M. tuberculosis DHFR. These studies suggest that compounds of this class are excellent potential leads for further development of drugs effective against M. tuberculosis.

The Role of nitro (NO2-), chloro (Cl), and fluoro (F) Substitution in the Design of Antileishmanial and Antichagasic Compounds

2020 ◽  
Vol 21 ◽  
Author(s):  
Boniface Pone ◽  
Ferreira Igne Elizabeth
Keyword(s):  
Chagas Disease ◽  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Pharmacokinetic Studies ◽  
Scientific Publications ◽  
Antitrypanosomal Activity ◽  
Chemical Groups

: Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas disease are among the most severe NTDs, and are caused by the Leishmania sp, and Trypanosoma cruzi, respectively. Glucantime, pentamidine and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance, and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, which chemical groups are known to improve the biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluoro-synthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth to mention that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro- and chloro-groups in the compound backbone. All in all, nitro and h0alogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts on in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies, and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.

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.

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