scholarly journals Amaryllidaceae alkaloids with anti-Trypanosoma cruzi activity

2020 ◽  
Author(s):  
Nieves Martinez-Peinado ◽  
Nuria Cortes-Serra ◽  
Laura Torras-Claveria ◽  
Maria-Jesus Pinazo ◽  
Joaquim Gascon ◽  
...  
Keyword(s):  
Natural Products ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Specific Activity ◽  
New Drugs ◽  
Host Cells ◽  
Amastigote Stage ◽  
Limited Efficacy ◽  
Single Compound ◽  
New Compounds

Abstract Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected disease that affects ~7 million people worldwide. Development of new drugs to treat the infection remains a priority since those currently available have frequent side effects and limited efficacy at the chronic stage. Natural products provide a pool of diversity structures to lead the chemical synthesis of novel molecules for this purpose. Herein we analyzed the anti- T. cruzi activity of 9 alkaloids derived from plants of the Amaryllidaceae family. Methods: the activity of each alkaloid was assessed by means of an anti- T. cruzi phenotypic assay. We further evaluated the compounds that inhibited the parasite growth on two distinct cytotoxicity assays to discard those that were toxic to host cells and assure parasite selectivity. Results: we identified a single compound (hippeastrine 2 ) that was selectively active against the parasite yielding selectivity indexes of 12.7 and 35.2 against Vero and HepG2 cells, respectively. Moreover, it showed specific activity against the amastigote stage (IC 50 = 3.31 μM). Conclusions: results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.

scholarly journals Amaryllidaceae alkaloids with anti-Trypanosoma cruzi activity

2020 ◽  
Author(s):  
Nieves Martinez-Peinado ◽  
Nuria Cortes-Serra ◽  
Laura Torras-Claveria ◽  
Maria-Jesus Pinazo ◽  
Joaquim Gascon ◽  
...  
Keyword(s):  
Natural Products ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Specific Activity ◽  
New Drugs ◽  
Host Cells ◽  
Amastigote Stage ◽  
Limited Efficacy ◽  
Single Compound ◽  
New Compounds

Abstract Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected disease that affects ~7 million people worldwide. Development of new drugs to treat the infection remains a priority since those currently available have frequent side effects and limited efficacy at the chronic stage. Natural products provide a pool of diversity structures to lead the chemical synthesis of novel molecules for this purpose. Herein we analyzed the anti- T. cruzi activity of 9 alkaloids derived from plants of the Amaryllidaceae family. Methods: the activity of each alkaloid was assessed by means of an anti- T. cruzi phenotypic assay. We further evaluated the compounds that inhibited the parasite growth on two distinct cytotoxicity assays to discard those that were toxic to host cells and assure parasite selectivity. Results: we identified a single compound (hippeastrine 2 ) that was selectively active against the parasite yielding selectivity indexes of 12.7 and 35.2 against Vero and HepG2 cells, respectively. Moreover, it showed specific activity against the amastigote stage (IC 50 = 3.31 μM). Conclusions: results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.

scholarly journals Amaryllidaceae alkaloids with anti-Trypanosoma cruzi activity.

2020 ◽  
Author(s):  
Nieves Martinez-Peinado ◽  
Nuria Cortes-Serra ◽  
Laura Torras-Claveria ◽  
Maria-Jesus Pinazo ◽  
Joaquim Gascon ◽  
...  
Keyword(s):  
Natural Products ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Specific Activity ◽  
New Drugs ◽  
Host Cells ◽  
Amastigote Stage ◽  
Limited Efficacy ◽  
Single Compound ◽  
New Compounds

Abstract Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected disease that affects ~7 million people worldwide. Development of new drugs to treat the infection remains a priority since those currently available have frequent side effects and limited efficacy at the chronic stage. Natural products provide a pool of diversity structures to lead the chemical synthesis of novel molecules for this purpose. Herein we analyzed the anti-T. cruzi activity of 9 alkaloids derived from plants of the Amaryllidaceae family.Methods: the activity of each alkaloid was assessed by means of an anti-T. cruzi phenotypic assay. We further evaluated the compounds that inhibited the parasite growth on two distinct cytotoxicity assays to discard those that were toxic to host cells and assure parasite selectivity.Results: we identified a single compound (hippeastrine 2) that was selectively active against the parasite yielding selectivity indexes of 12.7 and 35.2 against Vero and HepG2 cells, respectively. Moreover, it showed specific activity against the amastigote stage (IC50 = 3.31 μM).Conclusions: results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.

scholarly journals Amaryllidaceae alkaloids with anti-Trypanosoma cruzi activity

2020 ◽  
Author(s):  
Nieves Martinez-Peinado ◽  
Nuria Cortes-Serra ◽  
Laura Torras-Claveria ◽  
Maria-Jesus Pinazo ◽  
Joaquim Gascon ◽  
...  
Keyword(s):  
Natural Products ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
New Drugs ◽  
Host Cells ◽  
Amaryllidaceae Alkaloids ◽  
Cytotoxicity Assays ◽  
Limited Efficacy ◽  
Single Compound ◽  
New Compounds

Abstract Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected disease that affects ~7 million people worldwide. Development of new drugs to treat the infection remains a priority since those currently available have frequent side effects and limited efficacy at the chronic stage. Natural products provide a pool of diversity structures to lead the chemical synthesis of novel molecules for this purpose. Herein we analyzed the anti- T. cruzi activity of 9 alkaloids derived from plants of the Amaryllidaceae family. Methods: the activity of each alkaloid was assessed by means of a newly developed anti- T. cruzi phenotypic assay. We further evaluated the compounds that inhibited the parasite growth on two distinct cytotoxicity assays to discard those that were toxic to host cells and assure parasite selectivity. Results: we identified a single compound (hippeastrine 2 ) that was selectively active against the parasite yielding selectivity indexes of 12.7 and 35.2 against Vero and HepG2 cells, respectively. Conclusions: results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.

scholarly journals Bioluminescent:fluorescent Trypanosoma cruzi Reporter Strains as Tools for Exploring Chagas Disease Pathogenesis and Drug Activity

2020 ◽  
Vol 26 ◽  
Author(s):  
Martin C. Taylor ◽  
Alexander I. Ward ◽  
Francisco Olmo ◽  
Amanda F. Francisco ◽  
Shiromani Jayawardhana ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Parasite Burden ◽  
New Drugs ◽  
Host Cells ◽  
Complex Nature ◽  
Disease Pathogenesis ◽  
Drug Activity ◽  
Cellular Environment

: Chagas disease results from infection with the trypanosomatid parasite Trypanosoma cruzi. Progress in developing new drugs has been hampered by the long term and complex nature of the condition and by our limited understanding of parasite biology. Technical difficulties in assessing the parasite burden during the chronic stage of infection have also proved to be a particular challenge. In this context, the development of non-invasive, highly sensitive bioluminescence imaging procedures, based on parasites that express a red-shifted luciferase, has greatly enhanced our ability to monitor infections in experimental models. Applications of this methodology have led to new insights into tissue tropism and infection dynamics, and have been a major driver in drug development. The system has been further modified by the generation of parasite reporter lines that express bioluminescent:fluorescent fusion proteins, an advance that has allowed chronic infections in mice to be examined at a cellular level. By exploiting bioluminescence to identify the rare sites of tissue infection, and fluorescence to detect T. cruzi at the level of individual host cells in histological sections, it has been possible to investigate the replication and differentiation status of parasites in vivo and to examine the cellular environment of infection foci. In combination, these data are providing a framework for the detailed dissection of disease pathogenesis and drug activity.

scholarly journals The Dialogue of the Host-Parasite Relationship:Leishmaniaspp. andTrypanosoma cruziInfection

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Carlos Gustavo Vieira de Morais ◽  
Ana Karina Castro Lima ◽  
Rodrigo Terra ◽  
Rosiane Freire dos Santos ◽  
Silvia Amaral Gonçalves Da-Silva ◽  
...  
Keyword(s):  
Immune Response ◽  
Trypanosoma Cruzi ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Host Cells ◽  
Protective Response ◽  
Limited Efficacy ◽  
Causative Agents ◽  
Host Parasite ◽  
Emergence Of Resistance

The intracellular protozoaLeishmaniaspp. andTrypanosoma cruziand the causative agents of Leishmaniasis and Chagas disease, respectively, belong to the Trypanosomatidae family. Together, these two neglected tropical diseases affect approximately 25 million people worldwide. Whether the host can control the infection or develops disease depends on the complex interaction between parasite and host. Parasite surface and secreted molecules are involved in triggering specific signaling pathways essential for parasite entry and intracellular survival. The recognition of the parasite antigens by host immune cells generates a specific immune response.Leishmaniaspp. andT. cruzihave a multifaceted repertoire of strategies to evade or subvert the immune system by interfering with a range of signal transduction pathways in host cells, which causes the inhibition of the protective response and contributes to their persistence in the host. The current therapeutic strategies in leishmaniasis and trypanosomiasis are very limited. Efficacy is variable, toxicity is high, and the emergence of resistance is increasingly common. In this review, we discuss the molecular basis of the host-parasite interaction ofLeishmaniaandTrypanosoma cruziinfection and their mechanisms of subverting the immune response and how this knowledge can be used as a tool for the development of new drugs.

scholarly journals Antiparasitic Effect of Stilbene and Terphenyl Compounds against Trypanosoma cruzi Parasites

2021 ◽  
Vol 14 (11) ◽  
pp. 1199
Author(s):  
Federica Bruno ◽  
Germano Castelli ◽  
Fabrizio Vitale ◽  
Simone Catanzaro ◽  
Valeria Vitale Badaco ◽  
...  
Keyword(s):  
Natural Products ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Flow Cytometric Analysis ◽  
New Drugs ◽  
Normal Cells ◽  
Antiparasitic Activity ◽  
Intracellular Amastigotes ◽  
Caspase 1

Background: Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite Trypanosoma cruzi. No progress in the treatment of this pathology has been made since Nifurtimox was introduced more than fifty years ago, and this drug is considered very aggressive and may cause several adverse effects. This drug currently has severe limitations, including a high frequency of undesirable side effects and limited efficacy and availability, so research to discover new drugs for the treatment of Chagas disease is imperative. Many drugs available on the market are natural products as found in nature or compounds designed based on the structure and activity of these natural products. Methods: This study evaluated the in vitro antiparasitic activity of a series of previously synthesized stilbene and terphenyl compounds in T. cruzi epimastigotes and intracellular amastigotes. The action of the most selective compounds was investigated by flow cytometric analysis to evaluate the mechanism of cell death. The ability to induce apoptosis or caspase-1 inflammasomes was assayed in macrophages infected with T. cruzi after treatment, comparing it with that of Nifurtimox. Results: The stilbene ST18 was the most potent compound of the series. It was slightly less active than Nifurtimox in epimastigotes but most active in intracellular amastigotes. Compared to Nifurtimox, it was markedly less cytotoxic when tested in vitro on normal cells. ST18 was able to induce a marked increase in parasites positive for Annexin V and monodansylcadaverine. Moreover, ST18 induced the activation, in infected macrophages, of caspase-1, a conserved enzyme that plays a major role in controlling parasitemia, host survival and the onset of the adaptive immune response in Trypanosoma infection. Conclusions: The antiparasitic activity of ST18 together with its ability to activate caspase-1 in infected macrophages and its low toxicity toward normal cells makes this compound interesting for further clinical investigation.

scholarly journals Amaryllidaceae plants: a potential natural resource for the treatment of Chagas disease

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Nieves Martínez-Peinado ◽  
Nuria Cortes-Serra ◽  
Luciana R. Tallini ◽  
Maria-Jesus Pinazo ◽  
Joaquim Gascon ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Chemical Diversity ◽  
Host Cells ◽  
Cell Toxicity ◽  
Chronic Stage ◽  
Highly Active ◽  
Amastigote Stage ◽  
Medical Need ◽  
Chemical Content ◽  
Unique Chemical

Abstract Background Chagas disease is a neglected zoonosis caused by the parasite Trypanosoma cruzi. It affects over six million people, mostly in Latin America. Drugs available to treat T. cruzi infection have associated toxicity and questionable efficacy at the chronic stage. Hence, the discovery of more effective and safer drugs is an unmet medical need. For this, natural products represent a pool of unique chemical diversity that can serve as excellent templates for the synthesis of active molecules. Methods A collection of 79 extracts of Amaryllidaceae plants were screened against T. cruzi. Active extracts against the parasite were progressed through two cell toxicity assays based on Vero and HepG2 cells to determine their selectivity profile and discard those toxic to host cells. Anti-T. cruzi-specific extracts were further qualified by an anti-amastigote stage assay. Results Two extracts, respectively from Crinum erubescens and Rhodophiala andicola, were identified as highly active and specific against T. cruzi and its mammalian replicative form. Conclusions The results retrieved in this study encourage further exploration of the chemical content of these extracts in search of new anti-T. cruzi drug development starting points. Graphic abstract

scholarly journals Chemical Validation of Phosphodiesterase C as a Chemotherapeutic Target in Trypanosoma cruzi, the Etiological Agent of Chagas' Disease

2010 ◽  
Vol 54 (9) ◽  
pp. 3738-3745 ◽  
Author(s):  
Sharon King-Keller ◽  
Minyong Li ◽  
Alyssa Smith ◽  
Shilong Zheng ◽  
Gurpreet Kaur ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Catalytic Domain ◽  
Polypeptide Chain ◽  
Inflammatory Diseases ◽  
New Drugs ◽  
Volume Recovery ◽  
Chronic Pulmonary Diseases ◽  
Potential Inhibitors

ABSTRACT Trypanosoma cruzi phosphodiesterase (PDE) C (TcrPDEC), a novel and rather unusual PDE in which, unlike all other class I PDEs, the catalytic domain is localized in the middle of the polypeptide chain, is able to hydrolyze cyclic GMP (cGMP), although it prefers cyclic AMP (cAMP), and has a FYVE-type domain in its N-terminal region (S. Kunz et al., FEBS J. 272:6412-6422, 2005). TcrPDEC shows homology to the mammalian PDE4 family members. PDE4 inhibitors are currently under development for the treatment of inflammatory diseases, such as asthma, chronic pulmonary diseases, and psoriasis, and for treating depression and serving as cognitive enhancers. We therefore tested a number of compounds originally synthesized as potential PDE4 inhibitors on T. cruzi amastigote growth, and we obtained several useful hits. We then conducted homology modeling of T. cruzi PDEC and identified other compounds as potential inhibitors through virtual screening. Testing of these compounds against amastigote growth and recombinant TcrPDEC activity resulted in several potent inhibitors. The most-potent inhibitors were found to increase the cellular concentration of cAMP. Preincubation of cells in the presence of one of these compounds stimulated volume recovery after hyposmotic stress, in agreement with their TcrPDEC inhibitory activity in vitro, providing chemical validation of this target. The compounds found could be useful tools in the study of osmoregulation in T. cruzi. In addition, their further optimization could result in the development of new drugs against Chagas' disease and other trypanosomiases.

scholarly journals Neurotrophin Receptor TrkC Is an Entry Receptor for Trypanosoma cruzi in Neural, Glial, and Epithelial Cells

2011 ◽  
Vol 79 (10) ◽  
pp. 4081-4087 ◽  
Author(s):  
Craig Weinkauf ◽  
Ryan Salvador ◽  
Mercio PereiraPerrin
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Mammalian Cells ◽  
Chinese Hamster ◽  
Neuronal Cell ◽  
Host Cells ◽  
Neurotrophin Receptor ◽  
Content Type

ABSTRACTTrypanosoma cruzi, the agent of Chagas' disease, infects a variety of mammalian cells in a process that includes multiple cycles of intracellular division and differentiation starting with host receptor recognition by a parasite ligand(s). Earlier work in our laboratory showed that the neurotrophin-3 (NT-3) receptor TrkC is activated byT. cruzisurfacetrans-sialidase, also known as parasite-derived neurotrophic factor (PDNF). However, it has remained unclear whether TrkC is used byT. cruzito enter host cells. Here, we show that a neuronal cell line (PC12-NNR5) relatively resistant toT. cruzibecame highly susceptible to infection when overexpressing human TrkC but not human TrkB. Furthermore,trkCtransfection conferred an ∼3.0-fold intracellular growth advantage. Sialylation-deficient Chinese hamster ovarian (CHO) epithelial cell lines Lec1 and Lec2 also became much more permissive toT. cruziafter transfection with thetrkCgene. Additionally, NT-3 specifically blockedT. cruziinfection of the TrkC-NNR5 transfectants and of naturally permissive TrkC-bearing Schwann cells and astrocytes, as did recombinant PDNF. Two specific inhibitors of Trk autophosphorylation (K252a and AG879) and inhibitors of Trk-induced MAPK/Erk (U0126) and Akt kinase (LY294002) signaling, but not an inhibitor of insulin-like growth factor 1 receptor, abrogated TrkC-mediated cell invasion. Antibody to TrkC blockedT. cruziinfection of the TrkC-NNR5 transfectants and of cells that naturally express TrkC. The TrkC antibody also significantly and specifically reduced cutaneous infection in a mouse model of acute Chagas' disease. TrkC is ubiquitously expressed in the peripheral and central nervous systems, and in nonneural cells infected byT. cruzi, including cardiac and gastrointestinal muscle cells. Thus, TrkC is implicated as a functional PDNF receptor in cell entry, independently of sialic acid recognition, mediating broadT. cruziinfection bothin vitroandin vivo.

scholarly journals In Vitro and In Vivo Activities of E5700 and ER-119884, Two Novel Orally Active Squalene Synthase Inhibitors, against Trypanosoma cruzi

2004 ◽  
Vol 48 (7) ◽  
pp. 2379-2387 ◽  
Author(s):  
Julio A. Urbina ◽  
Juan Luis Concepcion ◽  
Aura Caldera ◽  
Gilberto Payares ◽  
Cristina Sanoja ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Public Health Problem ◽  
Squalene Synthase ◽  
Host Cells ◽  
In Vivo Studies ◽  
Inorganic Pyrophosphate ◽  
Orally Active

ABSTRACT Chagas' disease is a serious public health problem in Latin America, and no treatment is available for the prevalent chronic stage. Its causative agent, Trypanosoma cruzi, requires specific endogenous sterols for survival, and we have recently demonstrated that squalene synthase (SQS) is a promising target for antiparasitic chemotherapy. E5700 and ER-119884 are quinuclidine-based inhibitors of mammalian SQS that are currently in development as cholesterol- and triglyceride-lowering agents in humans. These compounds were found to be potent noncompetitive or mixed-type inhibitors of T. cruzi SQS with K i values in the low nanomolar to subnanomolar range in the absence or presence of 20 μM inorganic pyrophosphate. The antiproliferative 50% inhibitory concentrations of the compounds against extracellular epimastigotes and intracellular amastigotes were ca. 10 nM and 0.4 to 1.6 nM, respectively, with no effects on host cells. When treated with these compounds at the MIC, all of the parasite's sterols disappeared from the parasite cells. In vivo studies indicated that E5700 was able to provide full protection against death and completely arrested the development of parasitemia when given at a concentration of 50 mg/kg of body weight/day for 30 days, while ER-119884 provided only partial protection. This is the first report of an orally active SQS inhibitor that is capable of providing complete protection against fulminant, acute Chagas' disease.

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