Visceral leishmaniasis treatment: What do we have, what do we need and how to deliver it?

AbstractLeishmaniasis is one of the most neglected tropical disease in terms of drug discovery and development. Most antileishmanial drugs are highly toxic, present resistance issues or require hospitalization, being therefore not adequate to the field. Recently improvements have been achieved by combination therapy, reducing the time and cost of treatment. Nonetheless, new drugs are still urgently needed.In this review, we describe the current visceral leishmaniasis (VL) treatments and their limitations. We also discuss the new strategies in the drug discovery field including the development and implementation of high-throughput screening (HTS) assays and the joint efforts of international teams to deliver clinical candidates

Nitroheterocyclic compounds are more efficacious than CYP51 inhibitors against Trypanosoma cruzi: implications for Chagas disease drug discovery and development

Advocacy for better drugs and access to treatment has boosted the interest in drug discovery and development for Chagas disease, a chronic infection caused by the genetically heterogeneous parasite, Trypanosoma cruzi. in this work new in vitro assays were used to gain a better understanding of the antitrypanosomal properties of the most advanced antichagasic lead and clinical compounds, the nitroheterocyclics benznidazole, nifurtimox and fexinidazole sulfone, the oxaborole AN4169, and four ergosterol biosynthesis inhibitors -posaconazole, ravuconazole, EPL-BS967 and EPL-BS1246. Two types of assays were developed: one for evaluation of potency and efficacy in dose-response against a panel of T. cruzi stocks representing all current discrete typing units (DTUs), and a time-kill assay. Although less potent, the nitroheterocyclics and the oxaborole showed broad efficacy against all T. cruzi tested and were rapidly trypanocidal, whilst ergosterol biosynthesis inhibitors showed variable activity that was both compoundand strain-specific, and were unable to eradicate intracellular infection even after 7 days of continuous compound exposure at most efficacious concentrations. These findings contest previous reports of variable responses to nitroderivatives among different T. cruzi strains and further challenge the introduction of ergosterol biosynthesis inhibitors as new single chemotherapeutic agents for the treatment of Chagas disease.DNDiInstitut Pasteur Korea (IPK)Reconstruction Credit Institution-Federal Ministry of Education and Research (KfW-BMBF)/GermanyMedecins Sans Frontieres (Doctors without Borders)/InternationalKorean government (MSIP), Gyeonggi-doKISTIInst Pasteur Korea, Ctr Neglected Dis Drug Discovery CND3, Songnam, South KoreaCtr Nacl Pesquisa Energia & Mat, Lab Nacl Biociencias LNBio, Campinas, SP, BrazilUniversidade Federal de São Paulo UNIFESP, Depto Microbiol Imunol & Parasitol, São Paulo, BrazilDrugs Neglected Dis Initiat DNDi, Geneva, SwitzerlandUniversidade Federal de São Paulo UNIFESP, Depto Microbiol Imunol & Parasitol, São Paulo, BrazilKorean government (MSIP), Gyeonggi-do: 2007-00559Web of Scienc

Current and future chemotherapy for Chagas disease

Luís Gaspar is thankful to FCT for funding (scholarship reference: SFRH/BD/81604/2011). The research leading to these results has received funding from the European Community’s Seventh Framework Programme under grant agreement No.602773 (Project KINDRED) and No. 603240 (Project NMTrypI).American trypanosomiasis, commonly called Chagas disease, is one of the most neglected illnesses in the world and remains one of the most prevalent chronic infectious diseases of Latin America with thousands of new cases every year. The only treatments available have been introduced five decades ago. They have serious, undesirable side effects and disputed benefits in the chronic stage of the disease – a characteristic and debilitating cardiomyopathy and/or megavisceras. Several laboratories have therefore focused their efforts in finding better drugs. Although recent years have brought new clinical trials, these are few and lack diversity in terms of drug mechanism of action, thus resulting in a weak drug discovery pipeline. This fragility has been recently exposed by the failure of two candidates, posaconazole and E1224, to sterilely cure patients in phase 2 clinical trials. Such setbacks highlight the need for continuous, novel and high quality drug discovery and development efforts to discover better and safer treatments. In this article we will review past and current findings on drug discovery for Trypanosoma cruzi made by academic research groups, industry and other research organizations over the last half century. We will also analyze the current research landscape that is now better placed than ever to deliver alternative treatments for Chagas disease in the near futurePostprintPeer reviewe

Técnicas educacionais para o desenvolvimento das competências 4.0

Diferente das anteriores, a quarta Revolução Industrial é considerada revolucionária não apenas pelo termo referente à realização técnica, como os métodos de produção, formas de trabalhar das pessoas, mas também à capacidade de enfrentar os desafios atuais e futuros. Este artigo tem como objetivo aplicar um survey para avaliação das competências da Industria 4.0, estabelecer as competências mais relevantes por especialistas da área, aplicar o Analytic Hierarchy Process (AHP), método voltado para a decisão multicritério para a definição da técnica educacional mais eficiente. Os resultados obtidos apresentam que para as competências técnicas as práticas profissionais são mais eficientes enquanto para as competências comportamentais são as práticas acadêmicas

Telomeric Heterochromatin Propagation and Histone Acetylation Control Mutually Exclusive Expression of Antigenic Variation Genes in Malaria Parasites

SummaryMalaria parasites use antigenic variation to avoid immune clearance and increase the duration of infection in the human host. Variation at the surface of P. falciparum-infected erythrocytes is mediated by the differential control of a family of surface antigens encoded by var genes. Switching of var gene expression occurs in situ, mostly from telomere-associated loci, without detectable DNA alterations, suggesting that it is controlled by chromatin structure. We have identified chromatin modifications at telomeres that spread far into telomere-proximal regions, including var gene loci (>50 kb). One type of modification is mediated by a protein homologous to yeast Sir2 called PfSir2, which forms a chromosomal gradient of heterochromatin structure and histone hypoacetylation. Upon activation of a specific telomere-associated var gene, PfSir2 is removed from the promoter region and acetylation of histone occurs. Our data demonstrate that mutually exclusive transcription of var genes is linked to the dynamic remodeling of chromatin

Identification of Inhibitors to trypanosoma cruzi sirtuins based on compounds developed to human enzymes

Chagas disease is an illness caused by the protozoan parasite Trypanosoma cruzi, affecting more than 7 million people in the world. Benznidazole and nifurtimox are the only drugs available for treatment and in addition to causing several side effects, are only satisfactory in the acute phase of the disease. Sirtuins are NAD+-dependent deacetylases involved in several biological processes, which have become drug target candidates in various disease settings. T. cruzi presents two sirtuins, one cytosolic (TcSir2rp1) and the latter mitochondrial (TcSir2rp3). Here, we characterized the effects of human sirtuin inhibitors against T. cruzi sirtuins as an initial approach to develop specific parasite inhibitors. We found that, of 33 compounds tested, two inhibited TcSir2rp1 (15 and 17), while other five inhibited TcSir2rp3 (8, 12, 13, 30, and 32), indicating that specific inhibitors can be devised for each one of the enzymes. Furthermore, all inhibiting compounds prevented parasite proliferation in cultured mammalian cells. When combining the most effective inhibitors with benznidazole at least two compounds, 17 and 32, demonstrated synergistic effects. Altogether, these results support the importance of exploring T. cruzi sirtuins as drug targets and provide key elements to develop specific inhibitors for these enzymes as potential targets for Chagas disease treatment