Chagas Disease Research Articles

Preclinical evaluation of combined therapy with amiodarone and low-dose benznidazole in a mouse model of chronic Trypanosoma cruzi infection

Chagasic chronic cardiomyopathy (CCC) is the primary clinical manifestation of Chagas disease (CD), caused by Trypanosoma cruzi. Current therapeutic options for CD are limited to benznidazole (Bz) and nifurtimox. Amiodarone (AMD) has emerged as most effective drug for treating the arrhythmic form of CCC. To address the effects of Bz and AMD we used a preclinical model of CCC. Female C57BL/6 mice were infected with T. cruzi and subjected to oral treatment for 30 consecutive days, either as monotherapy or in combination. AMD in monotherapy decreased the prolonged QTc interval, the incidence of atrioventricular conduction disorders and cardiac hypertrophy. However, AMD monotherapy did not impact parasitemia, parasite load, TNF concentration and production of reactive oxygen species (ROS) in cardiac tissue. Alike Bz therapy, the combination of Bz and AMD (Bz/AMD), improved cardiac electric abnormalities detected T. cruzi-infected mice such as decrease in heart rates, enlargement of PR and QTc intervals and increased incidence of atrioventricular block and sinus arrhythmia. Further, Bz/AMD therapy ameliorated the ventricular function and reduced parasite burden in the cardiac tissue and parasitemia to a degree comparable to Bz monotherapy. Importantly, Bz/AMD treatment efficiently reduced TNF concentration in the cardiac tissue and plasma and had beneficial effects on immunological abnormalities. Moreover, in the cardiac tissue Bz/AMD therapy reduced fibronectin and collagen deposition, mitochondrial damage and production of ROS, and improved sarcomeric and gap junction integrity. Our study underlines the potential of the Bz/AMD therapy, as we have shown that combination increased efficacy in the treatment of CCC.

An Uncommon Presentation of Unstable Ventricular Tachycardia: Raising Awareness for Early Recognition of Chagas Disease

An Uncommon Presentation of Unstable Ventricular Tachycardia: Raising Awareness for Early Recognition of Chagas Disease

A Promising Amphotericin B Derivative Induces Morphological Alterations, Mitochondrial Damage, and Oxidative Stress In Vitro and Prevents Mice from Death Produced by a Virulent Strain of Trypanosoma cruzi

Chagas Disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, affecting 6–8 million people, mainly in Latin America. The medical treatment is based on two compounds, benznidazole and nifurtimox, with limited effectiveness and that produce severe side effects; consequently, there is an urgent need to develop new, safe, and effective drugs. Amphotericin B is the most potent antimycotic known to date. A21 is a derivative of this compound with the property of binding to ergosterol present in cell membranes of some organisms. In the search for a new therapeutic drug against T. cruzi, the objective of this work was to study the in vitro and in vivo effects of A21 derivative on T. cruzi. Our results show that the A21 increased the reactive oxygen species and reduced the mitochondrial membrane potential, affecting the morphology, metabolism, and cell membrane permeability of T. cruzi in vitro. Even more important was finding that in an in vivo murine model of infection, A21 in combination with benznidazole was able to reduce blood parasitemia, diminish the immune inflammatory infiltrate in skeletal muscle and rescue all the mice from death due to a virulent T. cruzi strain.

The beneficial effect of fluoxetine on behavioral and cognitive changes in chronic experimental Chagas disease unveils the role of serotonin fueling astrocyte infection by Trypanosoma cruzi.

In Chagas disease (CD), a neglected tropical disease caused by the parasite Trypanosoma cruzi, the development of mental disorders such as anxiety, depression, and memory loss may be underpinned by social, psychological, and biological stressors. Here, we investigated biological factors underlying behavioral changes in a preclinical model of CD. In T. cruzi-infected C57BL/6 mice, a kinetic study (5 to 150 days postinfection, dpi) using standardized methods revealed a sequential onset of behavioral changes: reduced innate compulsive behavior, followed by anxiety and depressive-like behavior, ending with progressive memory impairments. Hence, T. cruzi-infected mice were treated (120 to 150 dpi) with 10 mg/Kg/day of the selective serotonin reuptake inhibitor fluoxetine (Fx), an antidepressant that favors neuroplasticity. Fx therapy reversed the innate compulsive behavior loss, anxiety, and depressive-like behavior while preventing or reversing memory deficits. Biochemical, histological, and parasitological analyses of the brain tissue showed increased levels of the neurotransmitters GABA/glutamate and lipid peroxidation products and decreased expression of brain-derived neurotrophic factor in the absence of neuroinflammation at 150 dpi. Fx therapy ameliorated the neurochemical changes and reduced parasite load in the brain tissue. Next, using the human U-87 MG astroglioma cell line, we found no direct effect of Fx on parasite load. Crucially, serotonin/5-HT (Ser/5-HT) promoted parasite uptake, an effect increased by prior stimulation with IFNγ and TNF but abrogated by Fx. Also, Fx blocked the cytokine-driven Ser/5-HT-promoted increase of nitric oxide and glutamate levels in infected cells. We bring the first evidence of a sequential onset of behavioral changes in T. cruzi-infected mice. Fx therapy improves behavioral and biological changes and parasite control in the brain tissue. Moreover, in the central nervous system, cytokine-driven Ser/5-HT consumption may favor parasite persistence, disrupting neurotransmitter balance and promoting a neurotoxic environment likely contributing to behavioral and cognitive disorders.

Entomological investigation of triatomine fauna in rural communities in the state of Piauí, Brazilian semi-arid region

Objective: To describe the characteristics and distribution of triatomine fauna in rural communities of Simplício Mendes municipality, located in the state of Piauí, Brazilian semiarid region. Methods: This is a cross-sectional study and entomological survey conducted from 2022 to 2023. Insects were captured using active search method in all human dwellings, which were georeferenced, followed by characterized of species, sex, developmental stage, and identification of presence of infection by trypanosomatids. Results: All households (n=178) in 10 rural localities of the municipality were investigated, resulting in a household triatomine infestation rate of 14%. A total of 268 insects were collected, predominantly species from the Triatoma brasiliensis complex (n=190), immature developmental stage (n=172), and originating from peridomestic environments (n=250). The rate of triatomines with natural infection by Trypanosoma cruzi was 1.1%. Conclusion: The finding of infestation by species from the T. brasiliensis complex with higher concentration cohabiting extradomestic spaces, wide dispersion, and presence of natural infection by T. cruzi signals conditions for the maintenance of vector-borne transmission of Chagas disease in the municipality.

Leaps of Knowledge

Chagas Disease is the main cause of heart failure in the Western Hemisphere. Initially restricted to the American continent, the people's migration to the Northern Hemisphere caused the disease to become present in the five continents. A scientific revolution occurs when an important discovery removes an obstacle to the serial production of new scientific knowledge of social interest. Such a revolution creates a paradigm accepted after experimental analysis and verification by scientists investigating the subject. An example of a leap in knowledge was the discovery of the protozoan Trypanosoma cruzi, its invertebrate and vertebrate hosts, an agent of a new human disease recognized by Dr. Carlos Chagas at the beginning of the twentieth century. Certainly, the seminal work of Carlos Chagas inseminates enthusiasm that is essential to disturb the minds of scientists who produce leaps of knowledge about recondite aspects of Chagas disease at the University of Brasilia.

LMNA–RELATED DILATED CARDIOMYOPATHY PRESENTING WITH REGIONAL WALL AKINESIS AND TRANSMURAL LATE GADOLINIUM ENHANCEMENT

Abstract A 26–year–old girl was admitted at hospital in December 2022 for a syncopal episode. She referred fatigue and dyspnea in the last 2 months. EKG was markedly abnormal showing peripheral low voltages, poor R wave progression in prechordial leads, negative T waves V4–V6, DII, DIII and aVF, fragmented QRS (Fig.1). Echo showed moderately dilated left ventricle (LV) with apical akinesia and apical aneurysm (no thrombi) and hypo–akinesia and hyperechoic appearance of the middle segments of the infero–posterior and lateral wall (Fig.2a). EF was 38%. There was no family history for sudden cardiac death and cardiomyopathy. Creatine kinase and neurological examination were normal. The diagnostic work–up included: myocardial scintigraphy which showed fixed tracer uptake deficit at apical and posterolateral levels (Fig.2b); cardiac magnetic resonance (CMR): apical aneurysm with extended late gadolinium enhancement (LGE) due to fibrosis, focally transmural, on the left ventricle’s midapical and infero–lateral thinned–hypokinetic myocardial walls (Fig.3a, 3b); Coronary angiography showed no stenosis. Due to myocardial aneurysm in absence of CAD, Chagas disease was excluded. We performed LV endomyocardial biopsy which showed cardiomyopathic changes and replacement fibrosis. Due to fibrosis extension, complex ventricular extrasystoles detected on monitoring and syncope, ICD was implanted. Finally genetic testing showed c.1621C>Tp.Arg541Cys LMNA pathogenetic mutation leading to the diagnosis of LMNA–related LV cardiomyopathy, with extensive fibrosis in multiple areas of left ventricle including the apical segments at a very young age. Patients with LMNA mutation-related heart disease are characterized by conduction abnormalities, ventricular tachyarrhythmias (VA) and high risk of sudden cardiac death with mildly impaired systolic function, often without chamber dilation. About 88% LMNA– cardiomyopathy have typical myocardial fibrosis, predominantly in the mid-myocardium of the basal septum. However, our patient and previous reported cases with the same p.R541 LMNA mutation presents with a specific phenotype including regional LV akinesis, segmental transmural LGE, significant LV dilatation and systolic dysfunction and VA without conduction abnormality. Of note, EKG shows normal A–V conduction but low voltage and negative T waves in precordial and inferior leads. These features are not typical for LMNA–disease and underline the phenotypic variability of cardiomyopathies.

Exploring dietary differences among developmental stages of triatomines infected with Trypanosoma cruzi in different habitats

Chagas disease affects millions of people in Colombia and worldwide, with its transmission influenced by ecological, environmental, and anthropogenic factors. There is a notable correlation between vector transmission cycles and the habitats of insect vectors of the parasite. However, the scale at which these cycles operate remains uncertain. While individual triatomine ecotopes such as palms provide conditions for isolated transmission cycles, recent studies examining triatomine blood sources in various habitats suggest a more intricate network of transmission cycles, linking wild ecotopes with human dwellings. This study aims to provide further evidence on the complexity of the scale of Trypanosoma cruzi transmission cycles, by exploring the different blood sources among developmental stages of infected triatomines in different habitats. We evaluated infection rates, parasite loads, feeding sources, and the distribution of Rhodnius prolixus insects in Attalea butyracea palms across three distinct habitats in Casanare, Colombia: peridomestics, pastures, and woodlands. Our results show that there is no clear independence in transmission cycles in each environment. Analyses of feeding sources suggest the movement of insects and mammals (primarily bats and didelphids) among habitats. A significant association was found between habitat and instar stages in collected R. prolixus. The N1 stage was correlated with pasture and woodland, while the N4 stage was related to pasture. Additionally, adult insects exhibited higher T. cruzi loads than N1, N2, and N3. We observed higher T. cruzi loads in insects captured in dwelling and pasture habitats, compared with those captured in woodland areas. Effective Chagas disease control strategies must consider the complexity of transmission cycles and the interplay between domestic and sylvatic populations of mammals and vectors.

Epidemiological analysis of cases of acute Chagas Disease in Brazil between 2007 and 2022

Epidemiological analysis of cases of acute Chagas Disease in Brazil between 2007 and 2022

Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives.

Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi, hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1-9 displayed good potency (EC50T. cruzi amastigote <1 μM), and most compounds did not present significant cytotoxicity (CC50 MRC-5 = 32-64 μM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues.

Arrhythmogenic Manifestations of Chagas Disease: Perspectives From the Bench to Bedside.

Chagas cardiomyopathy caused by infection with the intracellular parasite Trypanosoma cruzi is the most common and severe expression of human Chagas disease. Heart failure, systemic and pulmonary thromboembolism, arrhythmia, and sudden cardiac death are the principal clinical manifestations of Chagas cardiomyopathy. Ventricular arrhythmias contribute significantly to morbidity and mortality and are the major cause of sudden cardiac death. Significant gaps still exist in the understanding of the pathogenesis mechanisms underlying the arrhythmogenic manifestations of Chagas cardiomyopathy. This article will review the data from experimental studies and translate those findings to draw hypotheses about clinical observations. Human- and animal-based studies at molecular, cellular, tissue, and organ levels suggest 5 main pillars of remodeling caused by the interaction of host and parasite: immunologic, electrical, autonomic, microvascular, and contractile. Integrating these 5 remodeling processes will bring insights into the current knowledge in the field, highlighting some key features for future management of this arrhythmogenic disease.

Mortality risk score for patients with Chagas cardiomyopathy and pacemaker.

Prognosis of Chronic Chagasic Cardiomyopathy (CCC) patients depends on functional and clinical factors. Bradyarrhythmia requiring pacemaker is a common complication. Prognosis of these patients is poorly studied, and mortality risk factors are unknown. We aimed to identify predictors of death and to define a risk score for mortality in a large cohort of CCC patients with pacemaker. It was an observational, unicentric and prospective study. The endpoint was all-cause mortality. Cox regression was used to identify predictors of death and to define a risk score. Bootstrapping method was used to internal score validation. We included 555 patients and after a mean follow-up of 3.7±1.5 years, 100 (18%) deaths occurred. Predictors of death were: right ventricular dysfunction (HR [hazard ratio] 2.24; 95%CI 1.41-3.53; P = 0.001); heart failure class III or IV (HR 2.16; 95% confidence interval [95%CI] 1.16-4.00; P = 0.014); renal disease (HR 2.14; 95%CI 1.24-3.68; P = 0.006); left ventricular end-systolic diameter > 44mm (HR 1.97; 95%CI 1.26-3.05; P = 0.003); atrial fibrillation (HR 1.94; 95%CI 1.25-2.99; P = 0.003) and cardiomegaly on X-ray (HR 1.87; 95%CI 1.10-3.17; P = 0.020). The score identified patients with: low (0-20 points), intermediate (21-30 points) and high risk (>31points). The optimism-corrected C-statistic of the predictive model was 0.751 (95% CI 0.696-0.806). Internal validation with bootstrapping revealed a calibration slope of 0.946 (95% CI 0.920-0.961), reflecting a small degree of over-optimism and C-statistic of 0.746 (95% CI 0.692-0.785). This study identified predictors of mortality in CCC patients with pacemaker defining a simple, validated and specific risk score.

Targeting Trypanothione Metabolism in Trypanosomatids.

Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected Tropical Diseases affecting millions of people worldwide, mainly in vulnerable territories of tropical and subtropical areas. In general, current treatments against these diseases are old-fashioned, showing adverse effects and loss of efficacy due to misuse or overuse, thus leading to the emergence of resistance. For these reasons, searching for new antitrypanosomatid drugs has become an urgent necessity, and different metabolic pathways have been studied as potential drug targets against these parasites. Considering that trypanosomatids possess a unique redox pathway based on the trypanothione molecule absent in the mammalian host, the key enzymes involved in trypanothione metabolism, trypanothione reductase and trypanothione synthetase, have been studied in detail as druggable targets. In this review, we summarize some of the recent findings on the molecules inhibiting these two essential enzymes for Trypanosoma and Leishmania viability.

The usefulness of patient-reported outcome measures in decision making in Chagas cardiomyopathy: a scoping review.

Chagas cardiomyopathy (ChC) presents many biopsychosocial complexities, highlighting the need to have patient self-report questions. This study demonstrates the scope of the use of patient-reported outcome measures (PROMs) in patients with ChC and highlights the main research gaps. This is a scoping review and the search strategy was performed in the Online Medical Literature Analysis and Retrieval System (MEDLINE), Excerpta Medica database (EMBASE), Accumulated Index of Nursing and Allied Health Literature (CINAHL), Cochrane Central, Latin American Literature and Caribbean in Health Sciences (LILACS) and Diagnostic Test Accuracy (DITA). The search identified 4484 studies and 20 studies met the inclusion criteria. The Short-Form of 36 items (SF-36) had potential prognostic value and the ability to identify systolic dysfunction. The Human Activity Profile was able to screen for functional impairment, and the New York Heart Association showed potential prognostic value. The SF-36 and Minnesota Living with Heart Failure Questionnaire were responsive to interventions. The pharmaceutical care affected adherence to treatment as assessed by the Morisky score and also for SF-36. Despite the increased use of PROMs, there are still a large number of gaps in the literature, and further studies using PROMs are needed.

First Report of Seropositivity to Trypanosoma cruzi in Mexican Afro-Descendants from Guerrero and Oaxaca States.

Mexican Afro-descendant is a population poorly studied in many aspects, between them the infectious diseases that they suffer. This population is mainly found in the country's Pacific (Oaxaca and Guerrero states) and Atlantic (Veracruz) coast. In these regions, a diversity of triatomine vectors of the Chagas disease is found. Also, all the genotypes of Trypanosoma cruzi DTUs have been reported. That is why the present study aimed to study the presence of antibodies against T. cruzi and cardiac pathology associated with the Chagas disease in the Mexican Afro-descendant population of Guerrero and Oaxaca. ELISA, Western blot, and recombinant antigen's ELISA were used to evaluate the seropositivity of these communities. Furthermore, an electrocardiographic study and evaluation of risk factors associated with T. cruzi infection in the Oaxaca and Guerrero populations were conducted. 26.77% of the analyzed population was positive for two serological tests. These percentages are higher than the previously reported for the mestizo population in similar studies. Electrocardiographic results showed cardiac disorder associated with the Chagas disease in the population. Also, risk factors were identified associated with the men's activities in the outdoor working areas.

Insecticidal activity of fluralaner (Exzolt®) administered to Gallus gallus domesticus against triatomines (Hemiptera, Reduviidae, Triatominae)

BackgroundTriatoma infestans, Triatoma brasiliensis, Triatoma pseudomaculata and Rhodnius prolixus are vectors of Trypanosoma cruzi, the etiological agent of Chagas disease. Chickens serve as an important blood food source for triatomines. This study aimed to assess the insecticidal activity of fluralaner (Exzolt®) administered to chickens against triatomines (R. prolixus, T. infestans, T. brasiliensis and T. pseudomaculata).MethodsTwelve non-breed chickens (Gallus gallus domesticus) were randomized based on weight into three groups: negative control (n = 4); a single dose of 0.5 mg/kg fluralaner (Exzolt®) (n = 4); two doses of 0.5 mg/kg fluralaner (Exzolt®) (n = 4). Nymphs of 3rd, 4th and 5th instars of R. prolixus, T. infestans, T. brasiliensis and T. pseudomaculata (all n = 10) were allowed to feed on chickens before treatment, and at intervals of 1, 7, 14, 21, 28, 35 and 56 days after treatment, with insect mortality determined.ResultsTreatment with two doses of fluralaner showed higher insecticidal efficacy against R. prolixus, T. infestans and T. brasiliensis compared to the single-dose treatment. Similar insecticidal efficacy was observed for T. pseudomaculata for one and two doses of fluralaner. Insecticidal activity of fluralaner (Exzolt®) against triatomine bugs was noted up to 21 and 28 days after treatment with one and two doses of fluralaner, respectively.ConclusionsThe results demonstrate that treatment of chickens with fluralaner (Exzolt®) induces insecticidal activity against triatomines for up to 28 days post-treatment, suggesting its potential use as a control strategy for Chagas disease in endemic areas.Graphical

Alternative Approaches for the Treatment of Chagas Disease

AbstractChagas disease (CD), or American trypanosomiasis, caused by the parasitic protozoa Trypanosoma cruzi, is a substantial global health burden. This comprehensive review explored the multifaceted landscape of CD treatment, providing a historical perspective on the development and discontinuation of benznidazole (BNZ) and nifurtimox (NF), the primary medications. Efforts towards a pediatric version of BZN in Brazil address demographic‐specific treatments, while concerns over drug resistance prompt the exploration of alternative medications like Amiodarone, Allopurinol, Posaconazole, Ravuconazole, and Fexinidazole, which were clinically tested as antichagasic drugs. In recent years, some of the synthesized derivative (1,3‐thiazoles, 4‐thiazolidinones, 2‐styrylquinolines, imidazole‐containing nitrophthalazine, and some others) were found to better activity as compared to standard drug. Traditional herbal alternatives (Resveratrol, curcumin, 1,8‐cineole, β‐pinene, and some others) rooted in traditional practices show promise, with various plant extracts exhibiting anti‐parasitic properties. The frontier of nanomedicine unfolds with studies on solid nanomedicines, PLA‐nanoparticles, ZIF‐8, BNZ carriers, and PLGA nanoparticles, showcasing improved drug delivery systems and controlled release mechanisms. The absence of a definitive vaccine accentuates ongoing research in recombinant antigens, peptide‐based vaccines, and nanoparticle formulations, with notable candidates like TcG1, TcG2, TcG4, MASPpep‐KLH, adenovirus vectors, Tc24 protein, and integrin activators. A novel strategy combining a recombinant protein vaccine with low dose BZN treatment presents promising results in a mouse model, emphasizing the urgency for further research and potential advancements in CD therapeutics.

Antitrypanosomal activity of new alkoxyhydroperoxides formed by cycloaddition of ozone into allyl moiety of eugenol

Eugenol, a natural phenylpropanoid found in several plants, was exposed to ozone atmosphere to afford three new alkoxyhydroperoxides and prevised homovanillin. The effect of these compounds against the protozoan parasite Trypanosoma cruzi resulted in EC50 values ranging from 7.4 to 10.5 μM, superior to the standard drug benznidazole (EC50 = 18.7 μM). Based on these results, it is possible to consider these compounds as scaffolds for the development of new drug candidates against Chagas disease.

A recombinant chimeric antigen constructed with B-cell epitopes from Mycobacterium leprae hypothetical proteins is effective for the diagnosis of leprosy

The diagnosis if leprosy is difficult, as it requires clinical expertise and sensitive laboratory tests. In this study, we develop a serological test for leprosy by using bioinformatics tools to identify specific B-cell epitopes from Mycobacterium leprae hypothetical proteins, which were used to construct a recombinant chimeric protein, M1. The synthetic peptides were obtained and showed good reactivity to detect leprosy patients, although the M1 chimera have showed sensitivity (Se) and specificity (Sp) values higher than 90.0% to diagnose both paucibacillary (PB) and multibacillary (MB) leprosy patients, but not those developing tegumentary or visceral leishmaniasis, tuberculosis, Chagas disease, malaria, histoplasmosis and aspergillosis, in ELISA experiments. Using sera from household contacts, values for Se and Sp were 100% and 65.3%, respectively. In conclusion, our proof-of-concept study has generated data that suggest that a new recombinant protein could be developed into a diagnostic antigen for leprosy.

Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease

According to the World Health Organization, Chagas disease (CD) is the most prevalent poverty-promoting neglected tropical disease. Alarmingly, climate change is accelerating the geographical spreading of CD causative parasite, Trypanosoma cruzi, which additionally increases infection rates. Still, CD treatment remains challenging due to a lack of safe and efficient drugs. In this work, we analyze the viability of T. cruzi Akt-like kinase (TcAkt) as drug target against CD including primary structural and functional information about a parasitic Akt protein. Nuclear Magnetic Resonance derived information in combination with Molecular Dynamics simulations offer detailed insights into structural properties of the pleckstrin homology (PH) domain of TcAkt and its binding to phosphatidylinositol phosphate ligands (PIP). Experimental data combined with Alpha Fold proposes a model for the mechanism of action of TcAkt involving a PIP-induced disruption of the intramolecular interface between the kinase and the PH domain resulting in an open conformation enabling TcAkt kinase activity. Further docking experiments reveal that TcAkt is recognized by human inhibitors PIT-1 and capivasertib, and TcAkt inhibition by UBMC-4 and UBMC-6 is achieved via binding to TcAkt kinase domain. Our in-depth structural analysis of TcAkt reveals potential sites for drug development against CD, located at activity essential regions.