A Paratransgenic Strategy for the Control of Chagas Disease

Hurwitz, Ivy; Fieck, Annabeth; Klein, Nichole; Jose, Christo; Kang, Angray S.; Durvasula, Ravi

doi:10.1155/2012/178930

Cited by 8 publications

(6 citation statements)

References 46 publications

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“…According to Hurwitz et al [49] the paratransgenic strategy has been used with other vector-borne disease systems such as sandfly-mediated leishmaniasis and sharpshootermediated Pierce's disease [50][51][52]. Additionally, the authors highlight the main strategies for the success of the paratrangenesis strategy.…”

Section: Reduviidaementioning

confidence: 99%

Host-Symbiont Interactions for Potentially Managing Heteropteran Pests

Prado

Zucchi

2012

Psyche: A Journal of Entomology

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Insects in the suborder Heteroptera, the so-called true bugs, include over 40,000 species worldwide. This insect group includes many important agricultural pests and disease vectors, which often have bacterial symbionts associated with them. Some symbionts have coevolved with their hosts to the extent that host fitness is compromised with the removal or alteration of their symbiont. The first bug/microbial interactions were discovered over 50 years ago. Only recently, mainly due to advances in molecular techniques, has the nature of these associations become clearer. Some researchers have pursued the genetic modification (paratransgenesis) of symbionts for disease control or pest management. With the increasing interest and understanding of the bug/symbiont associations and their ecological and physiological features, it will only be a matter of time before pest/vector control programs utilize this information and technique. This paper will focus on recent discoveries of the major symbiotic systems in Heteroptera, highlighting how the understanding of the evolutionary and biological aspects of these relationships may lead to the development of alternative techniques for efficient heteropteran pest control and suppression of diseases vectored by Heteroptera.

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Section: Reduviidaementioning

confidence: 99%

Host-Symbiont Interactions for Potentially Managing Heteropteran Pests

Prado

Zucchi

2012

Psyche: A Journal of Entomology

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“…cruzi trypomastigotes near the wound site. Following invasion of host cells in the bite wound or at mucous membranes, intracellular trypomastigotes undergo a morphological transformation into amastigotes and start to replicate [ 1 , 4 , 5 ]. After completing several rounds of intracellular division, the amastigotes transform into trypomastigotes that then leave the infected cell and initiate a new cycle of infection.…”

Section: Introductionmentioning

confidence: 99%

Utilizing Chemical Genomics to Identify Cytochrome b as a Novel Drug Target for Chagas Disease

et al. 2015

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Unbiased phenotypic screens enable identification of small molecules that inhibit pathogen growth by unanticipated mechanisms. These small molecules can be used as starting points for drug discovery programs that target such mechanisms. A major challenge of the approach is the identification of the cellular targets. Here we report GNF7686, a small molecule inhibitor of Trypanosoma cruzi, the causative agent of Chagas disease, and identification of cytochrome b as its target. Following discovery of GNF7686 in a parasite growth inhibition high throughput screen, we were able to evolve a GNF7686-resistant culture of T. cruzi epimastigotes. Clones from this culture bore a mutation coding for a substitution of leucine by phenylalanine at amino acid position 197 in cytochrome b. Cytochrome b is a component of complex III (cytochrome bc1) in the mitochondrial electron transport chain and catalyzes the transfer of electrons from ubiquinol to cytochrome c by a mechanism that utilizes two distinct catalytic sites, QN and QP. The L197F mutation is located in the QN site and confers resistance to GNF7686 in both parasite cell growth and biochemical cytochrome b assays. Additionally, the mutant cytochrome b confers resistance to antimycin A, another QN site inhibitor, but not to strobilurin or myxothiazol, which target the QP site. GNF7686 represents a promising starting point for Chagas disease drug discovery as it potently inhibits growth of intracellular T. cruzi amastigotes with a half maximal effective concentration (EC50) of 0.15 µM, and is highly specific for T. cruzi cytochrome b. No effect on the mammalian respiratory chain or mammalian cell proliferation was observed with up to 25 µM of GNF7686. Our approach, which combines T. cruzi chemical genetics with biochemical target validation, can be broadly applied to the discovery of additional novel drug targets and drug leads for Chagas disease.

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“…When this peptide is expressed by R. rhodnii , in the intestine of the triatomine vector, it induces the lysis of Epi and metacyclic trypomastigotes in the hindgut, and consequently clearance of the infection in the vector [ 186 , 190 ] (4A.3). This paratransgenic strategy could represent a novel alternative for control of vectorial transmission of T. cruzi , especially relevant because of the increasing resistance of vectors to insecticides [ 191 , 192 , 193 ]. All these AMPs isolated from insect vectors and their symbionts such as R. rhodnii exert their trypanocidal effect at micromolar concentrations; however, some of them, such as trialysin, are cytotoxic to host cells [ 20 , 22 , 186 , 187 , 190 ].…”

Section: Antimicrobial Peptides Against Kinetoplastids Causing Neglec...mentioning

confidence: 99%

Antimicrobial Peptides (AMPs): Potential Therapeutic Strategy against Trypanosomiases?

et al. 2023

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Trypanosomiases are a group of tropical diseases that have devastating health and socio-economic effects worldwide. In humans, these diseases are caused by the pathogenic kinetoplastids Trypanosoma brucei, causing African trypanosomiasis or sleeping sickness, and Trypanosoma cruzi, causing American trypanosomiasis or Chagas disease. Currently, these diseases lack effective treatment. This is attributed to the high toxicity and limited trypanocidal activity of registered drugs, as well as resistance development and difficulties in their administration. All this has prompted the search for new compounds that can serve as the basis for the development of treatment of these diseases. Antimicrobial peptides (AMPs) are small peptides synthesized by both prokaryotes and (unicellular and multicellular) eukaryotes, where they fulfill functions related to competition strategy with other organisms and immune defense. These AMPs can bind and induce perturbation in cell membranes, leading to permeation of molecules, alteration of morphology, disruption of cellular homeostasis, and activation of cell death. These peptides have activity against various pathogenic microorganisms, including parasitic protists. Therefore, they are being considered for new therapeutic strategies to treat some parasitic diseases. In this review, we analyze AMPs as therapeutic alternatives for the treatment of trypanosomiases, emphasizing their possible application as possible candidates for the development of future natural anti-trypanosome drugs.

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A Paratransgenic Strategy for the Control of Chagas Disease

Cited by 8 publications

References 46 publications

Host-Symbiont Interactions for Potentially Managing Heteropteran Pests

Host-Symbiont Interactions for Potentially Managing Heteropteran Pests

Utilizing Chemical Genomics to Identify Cytochrome b as a Novel Drug Target for Chagas Disease

Antimicrobial Peptides (AMPs): Potential Therapeutic Strategy against Trypanosomiases?

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