Walking a tightrope: drug discovery in visceral leishmaniasis

Drug Discovery Today, Год журнала: 2019, Номер 24(5), С. 1209 - 1216

Опубликована: Март 12, 2019

Язык: Английский

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Alkyl and Aryl Derivatives Based on p-Coumaric Acid Modification and Inhibitory Action against Leishmania braziliensis and Plasmodium falciparum

Molecules, Год журнала: 2020, Номер 25(14), С. 3178 - 3178

Опубликована: Июль 11, 2020

In low-income populations, neglected diseases are the principal cause of mortality. Of these, leishmaniasis and malaria, being parasitic, protozoan infections, affect millions people worldwide creating a public health problem. The present work evaluates leishmanicidal antiplasmodial action series twelve p-coumaric acid derivatives. tested derivatives, eight presented antiparasitic activities 1–3, 8–12. hexyl p-coumarate derivative (9) (4.14 ± 0.55 μg/mL; selectivity index (SI) = 2.72) showed highest potency against Leishmania braziliensis amastigote form. results molecular docking study suggest that this compound inhibits aldehyde dehydrogenase (ALDH), mitogen-activated kinase protein (MPK4), DNA topoisomerase 2 (TOP2), all which key enzymes in development braziliensis. data indicate these interact via Van der Waals bonds, hydrophobic interactions, hydrogen bonds with phenolic aliphatic parts same compound. other compounds analyzed, methyl (64.59 2.89 IS 0.1) demonstrated bioactivity Plasmodium falciparum. reveals esters presenting substructure promising for use synthesis derivatives good profiles.

Язык: Английский

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Next-Generation Leishmanization: Revisiting Molecular Targets for Selecting Genetically Engineered Live-Attenuated Leishmania

Microorganisms, Год журнала: 2023, Номер 11(4), С. 1043 - 1043

Опубликована: Апрель 16, 2023

Despite decades of research devoted to finding a vaccine against leishmaniasis, we are still lacking safe and effective for humans. Given this scenario, the search new prophylaxis alternative controlling leishmaniasis should be global priority. Inspired by leishmanization—a first generation strategy where live L. major parasites inoculated in skin protect reinfection—live-attenuated Leishmania candidates promising alternatives due their robust elicited protective immune response. In addition, they do not cause disease could provide long-term protection upon challenge with virulent strain. The discovery precise easy way perform CRISPR/Cas-based gene editing allowed selection safer null mutant live-attenuated obtained disruption. Here, revisited molecular targets associated vaccinal strains, discussing function, limiting factors ideal candidate next genetically engineered vaccines control leishmaniasis.

Язык: Английский

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Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(1), С. 402 - 419

Опубликована: Янв. 2, 2024

Trypanothione reductase (TR) is a suitable target for drug discovery approaches against leishmaniasis, although the identification of potent inhibitors still challenging. Herein, we harnessed fragment-based (FBDD) strategy to develop new TR inhibitors. Previous crystallographic screening identified fragments

Язык: Английский

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Py-CoMFA, docking, and molecular dynamics simulations of Leishmania (L.) amazonensis arginase inhibitors

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Май 21, 2024

Abstract Leishmaniasis is a disease caused by protozoan of the genus Leishmania , affecting millions people, mainly in tropical countries, due to poor social conditions and low economic development. First-line chemotherapeutic agents involve highly toxic pentavalent antimonials, while treatment failure emergence drug-resistant strains. arginase (ARG) enzyme vital pathogenicity contributes higher infection rate, thus representing potential drug target. This study helps designing ARG inhibitors for leishmaniasis. Py-CoMFA (3D-QSAR) models were constructed using 34 from different chemical classes against L. (L.) amazonensis ( La ARG). The 3D-QSAR predictions showed an excellent correlation between experimental calculated pIC 50 values. molecular docking identified favorable hydrophobicity contribution phenyl cyclohexyl groups as substituents allosteric site. Molecular dynamics simulations selected protein–ligand complexes conducted understand derivatives’ interaction modes affinity both active sites. Two cinnamide compounds, 7g 7k identified, with similar structures reference 4h site inhibitor. These compounds can guide development more effective antileishmanial drugs.

Язык: Английский

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Discovery and Genetic Validation of Chemotherapeutic Targets for Chagas' Disease

Frontiers in Cellular and Infection Microbiology, Год журнала: 2019, Номер 8

Опубликована: Янв. 7, 2019

There is an urgent need to develop new treatments for Chagas´ disease. To identify drug targets, it important understand the basic biology of Trypanosoma cruzi, in particular with respect biological pathways or proteins that are essential its survival within host. This review provides a streamlined approach identifying targets using freely available chemogenetic databases and outlines relevant characteristics ideal chemotherapeutic target. Among those their essentiality, druggability, availability structural information, selectivity. At moment only 16 genes have been found as by gene disruption T. cruzi. TDR Targets database, chemogenomics resource neglected diseases, information about published structures these was three annotation validated inhibitors two. These activity against parasitic stages present We then analyzed considered promising search targets: 1. Ergosterol biosynthesis, 2. Resistance oxidative stress, 3. Synthesis surface glycoconjugates. annotated all participate them, identified druggable, incorporated evidence from either brucei, Leishmania spp. supports hypothesis cruzi survival.

Язык: Английский

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State‐of‐the‐art CRISPR/Cas9 Technology for Genome Editing in Trypanosomatids

Journal of Eukaryotic Microbiology, Год журнала: 2019, Номер 66(6), С. 981 - 991

Опубликована: Июнь 18, 2019

Abstract CRISPR /Cas9 technology has revolutionized biology. This prokaryotic defense system against foreign DNA been repurposed for genome editing in a broad range of cell tissues and organisms. Trypanosomatids are flagellated protozoa belonging to the order Kinetoplastida . Some its most representative members cause important human diseases affecting millions people worldwide, such as Chagas disease, sleeping sickness different forms leishmaniases. Trypanosomatid infections represent an enormous burden public health there no effective treatments they cause. Since emergence technology, genetic manipulation these parasites notably improved. As consequence, is now playing key role functional study proteins, characterization metabolic pathways, validation alternative targets antiparasitic interventions, parasite biology pathogenesis. In this work we review strategies that have used adapt Trypanosoma cruzi , brucei, Leishmania spp., well research progress achieved using approaches. Thereby, will present state‐of‐the‐art molecular tools available trypanosomatids finally point out future perspectives field.

Язык: Английский

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Computational approaches for drug discovery against trypanosomatid-caused diseases

Parasitology, Год журнала: 2020, Номер 147(6), С. 611 - 633

Опубликована: Фев. 12, 2020

Abstract During three decades, only about 20 new drugs have been developed for malaria, tuberculosis and all neglected tropical diseases (NTDs). This critical situation was reached because NTDs represent 10% of health research investments; however, they comprise 90% the global disease burden. Computational simulations applied in virtual screening (VS) strategies are very efficient tools to identify pharmacologically active compounds or indications already administered other diseases. One advantages this approach is low time-consuming low-budget first stage, which filters testing experimentally a group candidate with high chances binding target present trypanocidal activity. In work, we review most common VS that used identification special emphasis on those trypanosomiasis leishmaniasis. based selected protein targets their ligands explained, including method selection criteria, examples successful campaigns NTDs, list validated molecular drug development repositioned trypanosomatid-caused Thereby, here state-of-the-art repurposing conclude pointing out future perspectives field.

Язык: Английский

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Bar-seq strategies for the LeishGEdit toolbox

Molecular and Biochemical Parasitology, Год журнала: 2020, Номер 239, С. 111295 - 111295

Опубликована: Июль 10, 2020

Язык: Английский

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Prediction of Antileishmanial Compounds: General Model, Preparation, and Evaluation of 2-Acylpyrrole Derivatives

Journal of Chemical Information and Modeling, Год журнала: 2022, Номер 62(16), С. 3928 - 3940

Опубликована: Авг. 10, 2022

In this work, the SOFT.PTML tool has been used to pre-process a ChEMBL dataset of pre-clinical assays antileishmanial compound candidates. A comparative study different ML algorithms, such as logistic regression (LOGR), support vector machine (SVM), and random forests (RF), shown that IFPTML-LOGR model presents excellent values specificity sensitivity (81-98%) in training validation series. The use software illustrated with practical case focused on series 28 derivatives 2-acylpyrroles 5a,b, obtained through Pd(II)-catalyzed C-H radical acylation pyrroles. Their vitro leishmanicidal activity against visceral (L. donovani) cutaneous amazonensis) leishmaniasis was evaluated finding compounds 5bc (IC50 = 30.87 μM, SI > 10.17) 5bd 16.87 10.67) were approximately 6-fold more selective than drug reference (miltefosine) L. amazonensis promastigotes. addition, most showed low cytotoxicity, CC50 100 μg/mL J774 cells. Interestingly, IFPMTL-LOGR predicts correctly relative biological these acylpyrroles. computational high-throughput screening (cHTS) 5a,b performed calculating >20,700 scores vs large space 647 involving multiple Leishmania species, cell lines, potential target proteins. Overall, demonstrates all-in-one strategy is useful obtain IFPTML models friendly interface making work easier faster before. present also points new lead worthy further optimization hits.

Язык: Английский

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