Cell death pathways in pathogenic trypanosomatids: lessons of (over)kill

Cell Death and Disease, Год журнала: 2019, Номер 10(2)

Опубликована: Янв. 30, 2019

Especially in tropical and developing countries, the clinically relevant protozoa Trypanosoma cruzi (Chagas disease), brucei (sleeping sickness) Leishmania species (leishmaniasis) stand out infect millions of people worldwide leading to critical social-economic implications. Low-income populations are mainly affected by these three illnesses that neglected pharmaceutical industry. Current anti-trypanosomatid drugs present variable efficacy with remarkable side effects almost lead treatment discontinuation, justifying a continuous search for alternative compounds interfere essential specific parasite pathways. In this scenario, triggering trypanosomatid cell death machinery emerges as promising approach, although exact mechanisms involved unicellular eukaryotes still unclear well controversial biological importance programmed (PCD). review, autophagy, apoptosis-like necrosis found pathogenic trypanosomatids discussed, their roles successful infection. Based on published genomic proteomic maps, panel molecules was constructed under different experimental conditions. The lack PCD molecular regulators executioners parasites up now has led being classified an unregulated process or incidental necrosis, despite all morphological evidence published. context, participation metacaspases also not described, proteases play crucial role proliferation differentiation processes. On other hand, autophagic phenotype been described great variety stress conditions (drugs, starvation, among others) suggesting is turnover damaged structures pathway. Death may be pathogenesis, identification parasite-specific could represent rational attractive target drug development diseases.

Язык: Английский

---

The current drug discovery landscape for trypanosomiasis and leishmaniasis: Challenges and strategies to identify drug targets

Drug Development Research, Год журнала: 2020, Номер 83(2), С. 225 - 252

Опубликована: Апрель 6, 2020

Abstract Human trypanosomiasis and leishmaniasis are vector‐borne neglected tropical diseases caused by infection with the protozoan parasites Trypanosoma spp. Leishmania spp., respectively. Once restricted to endemic areas, these now distributed worldwide due human migration, climate change, anthropogenic disturbance, causing significant health economic burden globally. The current chemotherapy used treat has limited efficacy, drug resistance is spreading. Hence, new drugs urgently needed. Phenotypic compound screenings have prevailed as leading method discover candidates against diseases. However, publication of complete genome sequences multiple strains, advances in application CRISPR/Cas9 technology, vivo bioluminescence‐based imaging set stage for advancing target‐based discovery. This review analyses limitations narrow pool available presently treating It describes drug‐based clinical trials highlighting most promising leads. Furthermore, presents a focused discussion on important biological pharmacological challenges that discovery programs must overcome advance candidates. Finally, it examines advantages modern research tools designed identify validate essential genes targets, including genomic editing applications imaging.

Язык: Английский

---

Antileishmanial Drug Discovery and Development: Time to Reset the Model?

Microorganisms, Год журнала: 2021, Номер 9(12), С. 2500 - 2500

Опубликована: Дек. 2, 2021

Leishmaniasis is a vector-borne parasitic disease caused by Leishmania species. The affects humans and animals, particularly dogs, provoking cutaneous, mucocutaneous, or visceral processes depending on the sp. host immune response. No vaccine for available, control relies mainly chemotherapy. However, currently used drugs are old, some toxic, safer presentations largely unaffordable most severely affected human populations. Moreover, its efficacy has shortcomings, it been challenged growing reports of resistance therapeutic failure. This manuscript presents an overview drugs, prevailing model to develop new antileishmanial low efficiency, impact deconstruction drug pipeline high failure rate potential drugs. To improve predictive value preclinical research in chemotherapy leishmaniasis, several proposals presented circumvent critical hurdles—namely, lack common goals collaborative research, public–private partnership; fragmented efforts; use inadequate surrogate models, especially vivo trials; shortcomings target product profile (TPP) guides.

Язык: Английский

---

Can Cysteine Protease Cross-Class Inhibitors Achieve Selectivity?

Journal of Medicinal Chemistry, Год журнала: 2019, Номер 62(23), С. 10497 - 10525

Опубликована: Июль 30, 2019

Cysteine proteases are important targets for the discovery of novel therapeutics many human diseases. From parasitic diseases to cancer, cysteine follow a common mechanism, formation an encounter complex with subsequent nucleophilic reactivity catalytic thiol group toward carbonyl carbon peptide bond or electrophilic inhibitor. Modulation target enzymes occurs preferably by covalent modification, which imposes challenges in balancing cross-reactivity and selectivity. Given resurgence irreversible inhibitors, can they impair off-target effects reversible inhibitors better route selectivity? This Perspective addresses how small molecule may achieve selectivity different cathepsins, cruzain, rhodesain, falcipain-2. We discuss target- ligand-based designs emphasizing repurposing from one protease others.

Язык: Английский

---

Marine alkaloids as bioactive agents against protozoal neglected tropical diseases and malaria

Natural Product Reports, Год журнала: 2021, Номер 38(12), С. 2214 - 2235

Опубликована: Янв. 1, 2021

This Review discusses the isolation and bioactivity of marine alkaloids against protozoan parasite diseases, chemical syntheses that enable further development these scaffolds as drug leads.

Язык: Английский

---

Anti-inflammatory and immunomodulatory effects of mesenchymal stem cell therapy on parasitic drug resistance

Expert Review of Anti-infective Therapy, Год журнала: 2024, Номер 22(6), С. 435 - 451

Опубликована: Май 28, 2024

The emergence of antiparasitic drug resistance poses a concerning threat to animals and humans. Mesenchymal Stem Cells (MSCs) have been widely used treat infections in humans, pets, livestock. Although this is an emerging field study, the current review outlines possible mechanisms examines potential synergism combination therapies harmful effects such approach.

Язык: Английский

---

Need for sustainable approaches in antileishmanial drug discovery

Parasitology Research, Год журнала: 2019, Номер 118(10), С. 2743 - 2752

Опубликована: Авг. 31, 2019

Язык: Английский

---

Carajurin Induces Apoptosis in Leishmania amazonensis Promastigotes through Reactive Oxygen Species Production and Mitochondrial Dysfunction

Pharmaceuticals, Год журнала: 2022, Номер 15(3), С. 331 - 331

Опубликована: Март 9, 2022

Carajurin is the main constituent of Arrabidaea chica species with reported anti-Leishmania activity. However, its mechanism action has not been described. This study investigated mechanisms carajurin against promastigote forms Leishmania amazonensis. was effective promastigotes IC50 7.96 ± 1.23 μg.mL-1 (26.4 µM), and cytotoxic concentration for peritoneal macrophages 258.2 1.20 (856.9 µM) after 24 h treatment. Ultrastructural evaluation highlighted pronounced swelling kinetoplast loss electron-density in L. amazonensis induced by It observed that leads to a decrease mitochondrial membrane potential (p = 0.0286), an increase reactive oxygen production cell death late apoptosis 0.0095) parasites. Pretreatment antioxidant NAC prevented ROS significantly reduced carajurin-induced death. The electrochemical density functional theory (DFT) data contributed support molecular associated generation, which it possible observe correlation between LUMO energy electroactivity presence oxygen. All these results suggest targets mitochondria In addition, when assessed drug-likeness, follows Lipinski''s rule five, Ghose, Veber, Egan, Muegge criteria.

Язык: Английский

---

The Potential Use of Peptides in the Fight against Chagas Disease and Leishmaniasis

Pharmaceutics, Год журнала: 2024, Номер 16(2), С. 227 - 227

Опубликована: Фев. 4, 2024

Chagas disease and leishmaniasis are both neglected tropical diseases that affect millions of people around the world. Leishmaniasis is currently second most widespread vector-borne parasitic after malaria. The World Health Organization records approximately 0.7-1 million newly diagnosed cases each year, resulting in 20,000-30,000 deaths. Also, 25 worldwide at risk an estimated 6 infected with

Язык: Английский

---

Leishmaniasis and Chagas Disease – Neglected Tropical Diseases: Treatment Updates

Current Topics in Medicinal Chemistry, Год журнала: 2019, Номер 19(3), С. 174 - 177

Опубликована: Март 28, 2019

The World Health Organization (WHO) [1] has listed 20 neglected tropical diseases (NTDs), including infections caused by viruses, bacteria, fungi and protozoa. Together, these illnesses put at risk more than 1.4 billion people that live in absolute poverty, primarily developing countries. Despite the high morbidity costs with treatment/hospitalization, it is been evident private sector does not have suitable interest financing programs against many of NTDs. This regrettable fact occurs because conditions affect a portion population living on margins therefore little financial return obtained by development new drugs diagnostic tests. market strategy contributes to spread poverty generates social stigma this ....

Язык: Английский

---