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

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Current Landscape of Methods to Evaluate Antimicrobial Activity of Natural Extracts

Molecules, Год журнала: 2023, Номер 28(3), С. 1068 - 1068

Опубликована: Янв. 20, 2023

Natural extracts have been and continue to be used treat a wide range of medical conditions, from infectious diseases cancer, based on their convenience therapeutic potential. products derived microbes, plants, animals offer broad variety molecules chemical compounds. are not only one the most important sources for innovative drug development animal human health, but they also an inspiration synthetic biology chemistry scientists towards discovery new bioactive compounds pharmaceuticals. This is particularly relevant in current context, where antimicrobial resistance has risen as global health problem. Thus, efforts being directed toward studying natural compounds’ composition potential generate drugs with better efficacy lower toxicity than existing molecules. Currently, methodologies analyze vitro activity determine suitability agents. Despite traditional technologies employed, technological advances contributed implementation methods able circumvent issues related analysis capacity, time, sensitivity, reproducibility. review produces updated conventional evaluate

Язык: Английский

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Recent Advances in Chemotherapeutics for Leishmaniasis: Importance of the Cellular Biochemistry of the Parasite and Its Molecular Interaction with the Host

Pathogens, Год журнала: 2023, Номер 12(5), С. 706 - 706

Опубликована: Май 12, 2023

Leishmaniasis, a category 1 neglected protozoan disease caused by kinetoplastid pathogen called Leishmania, is transmitted through dipteran insect vectors (phlebotomine, sand flies) in three main clinical forms: fatal visceral leishmaniasis, self-healing cutaneous and mucocutaneous leishmaniasis. Generic pentavalent antimonials have long been the drug of choice against leishmaniasis; however, their success plagued with limitations such as resistance severe side effects, which makes them redundant frontline therapy for endemic Alternative therapeutic regimens based on amphotericin B, miltefosine, paromomycin also approved. Due to unavailability human vaccines, first-line chemotherapies antimonials, pentamidine, B are only options treat infected individuals. The higher toxicity, adverse perceived cost these pharmaceutics, coupled emergence parasite relapse, it urgent identify new, rationalized targets improvement management palliative care patients. This has become an emergent need more relevant due lack information validated molecular markers monitoring surveillance changes sensitivity resistance. present study reviewed recent advances chemotherapeutic targeting novel drugs using several strategies including bioinformatics gain new insight into Leishmania unique enzymes biochemical pathways that distinct from those its mammalian hosts. In light limited number available antileishmanial drugs, identification studying cellular aspects host critical design specific inhibitors controlling parasite. characterization Leishmania-specific can be used tools read possible targets. this review, we discuss metabolic unique, essential, linked survival analyses.

Язык: Английский

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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

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Protective or Detrimental? Understanding the Role of Host Immunity in Leishmaniasis

Microorganisms, Год журнала: 2019, Номер 7(12), С. 695 - 695

Опубликована: Дек. 13, 2019

The intracellular protozoan parasites of the genus Leishmania are causative agents leishmaniasis, a vector-borne disease major public health concern, estimated to affect 12 million people worldwide. clinical manifestations leishmaniasis highly variable and can range from self-healing localized cutaneous lesions life-threatening disseminated visceral disease. Once introduced into skin by infected sandflies, interact with variety immune cells, such as neutrophils, monocytes, dendritic cells (DCs), macrophages. resolution infection requires finely tuned interplay between innate adaptive culminating activation microbicidal functions parasite clearance within host cells. However, several factors derived host, insect vector, spp., including presence double-stranded RNA virus (LRV), modulate immunity influence outcome. In this review, we discuss mechanisms underlying main forms some involved establishment severity, potential approaches for vaccine drug development focused on immunity.

Язык: Английский

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Regulation of Translation in the Protozoan Parasite Leishmania

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(8), С. 2981 - 2981

Опубликована: Апрель 23, 2020

Leishmaniasis represents a serious health problem worldwide and drug resistance is growing concern. Leishmania parasites use unusual mechanisms to control their gene expression. In contrast many other species, they do not have transcriptional regulation. The lack of mainly compensated by post-transcriptional mechanisms, including tight translational regulation mRNA stability/translatability RNA-binding proteins. Modulation translation plays major role in parasite survival adaptation dramatically different environments during change host; however, our knowledge fine molecular remains limited. Here, we review the current progress understanding how changes machinery promote differentiation transmission from sand fly mammalian host, discuss reprogramming can contribute development resistance.

Язык: Английский

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Potential of the natural products against leishmaniasis in Old World - a review of in-vitro studies

Pathogens and Global Health, Год журнала: 2020, Номер 114(4), С. 170 - 182

Опубликована: Апрель 27, 2020

Leishmaniasis is a vector-borne disease among the 10 most Neglected Tropical Diseases with diverse clinical manifestations caused by protozoan parasites of Leishmania genus. Around 80% leishmaniasis cases are found in Old World affecting populations mainly low and middle-income countries. Its control relies mostly on chemotherapy which still presents many drawbacks. Natural products may offer an inexhaustible source chemical diversity therapeutic potential. Despite lack knowledge traditional activity against parasites, reports describe search for natural extracts compounds antileishmanial properties promastigote amastigote parasite forms. This review summarizes research 74 publications last decade (2008-2018) focused identification endemic plant-derived that active responsible cutaneous visceral leishmaniasis. The present combines data 423 plants species, belonging to 94 different families, including large range crude lead isolation 86 compounds. Most studied came from Asia promising plant families were Asteraceae Lamiaceae. From point view, terpenoids frequently isolated products. These studies suggest flora rich new scaffolds future treatment as well other warranting further investigation.

Язык: Английский

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Metabolic Pathways of Leishmania Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates

Pharmaceutics, Год журнала: 2022, Номер 14(8), С. 1590 - 1590

Опубликована: Июль 30, 2022

Leishmaniasis is a tropical disease caused by protozoan parasite Leishmania that transmitted via infected female sandflies. At present, leishmaniasis treatment mainly counts on chemotherapy. The currently available drugs against are costly, toxic, with multiple side effects, and limitations in the administration route. rapid emergence of drug resistance has severely reduced potency anti-leishmanial drugs. As result, there pressing need for development novel high potency, low cost, acceptable toxicity, good pharmacokinetics features. Due to availability preclinical data, repurposing valuable approach speeding up effective through pointing new targets less time, having costs risk. Metabolic pathways this play crucial role growth proliferation species during various stages their life cycle. Based genomics/proteomics information, known pathways-based (sterol biosynthetic pathway, purine salvage glycolysis, GPI biosynthesis, hypusine, polyamine biosynthesis) Leishmania-specific proteins could be targeted were used other diseases, resulting finding promising therapeutics. present review discusses metabolic some candidates targeting these effectively potent future.

Язык: Английский

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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

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Tratamento da leishmaniose, limitações da terapêutica atual e a necessidade de novas alternativas: Uma revisão narrativa

Research Society and Development, Год журнала: 2021, Номер 10(7), С. e29510716543 - e29510716543

Опубликована: Июнь 22, 2021

As leishmanioses são um grupo de doenças negligenciadas causadas por protozoários intracelulares do gênero Leishmania. Suas principais formas clínicas a tegumentar (LT) e visceral (LV). Atualmente terapêutica contra leishmaniose baseia-se na utilização cinco fármacos: os antimoniais pentavalentes, anfotericina B sua formulação lipossômica, miltefosina, paromomicina pentamidina. Estes compostos apresentam limitações que dificultam adesão paciente ao tratamento como: elevada toxicidade necessidade administração prolongada via parenteral, além da possível seleção cepas resistentes. Assim, utilizando revisão narrativa literatura, buscou-se elucidar panorama atual leishmaniose, seus mecanismos ação elucidados, atribuída, efeitos adversos vias administração. Para tanto, dados mais atualizados disponíveis literatura foram trazidos para facilitar o acesso às informações sobre as opções terapêuticas, das novas alternativas terapêuticas perspectivas vacinas esta doença negligenciada.

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