Methods of macrophages activation and their modulation for the prospection of new antileishmania drugs: a review

2021 ◽  
Vol 37 ◽  
pp. e37077
Author(s):  
Michel Muálem de Moraes Alves ◽  
Daniel Dias Rufino Arcanjo ◽  
Rita Cássia Viana de Carvalho ◽  
Layane Valéria Amorim ◽  
Ingredy Lopes dos Santos ◽  
...  
Keyword(s):  
Immune Response ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Tropical Diseases ◽  
First Line ◽  
Phagocytic Capacity ◽  
Activity Increase ◽  
Parasitic Zoonoses ◽  
Infected Cells ◽  
Cellular Immune

Leishmaniasis are a group of parasitic zoonoses provoked by protozoa from Leishmania genus and belonging to the group of neglected tropical diseases. The search and development for new drugs is necessary not only to investigate the activity against only the parasite, but also to investigate the possible synergistic effect of new drugs with the immune response of the host. In the present review, macrophages are pointed out as potential targets of the investigation of new antileishmanial drugs, and some methodologies in order to assess their activation as response to Leishmania-infected cells are presented. Macrophages are an important role in the cellular immune response, since they are cells from mononuclear phagocytic system, the first line of defense of the host, against parasites from Leishmania genus. Phagocytic capacity, lysosomal activity, increase of nitric oxide and intracellular calcium levels are parameters regarding assessment of macrophages activation which allow them to be more hostile in order to solve the infection and lead the patient to cure. In this context, we bring 19 substances already investigated and that activate macrophages, what makes them promising in the antileishmanial treatment. Therefore, assessment of macrophages activation, are important tools for discovery of immunomodulatory compounds which have potential to act in synergism with host immune response. Such compounds might be promising as monotherapy in the treatment of leishmaniasis, as well as being used as adjuvants in vaccines and/or in combination with conventional drugs.

scholarly journals WIPO Re:Search: Catalyzing Public-Private Partnerships to Accelerate Tropical Disease Drug Discovery and Development

2019 ◽  
Vol 4 (1) ◽  
pp. 53 ◽  
Author(s):  
Cathyryne Manner ◽  
Katy Graef ◽  
Jennifer Dent
Keyword(s):  
Drug Discovery ◽  
Intellectual Property ◽  
Neglected Tropical Diseases ◽  
Tropical Disease ◽  
New Drugs ◽  
World Intellectual Property Organization ◽  
Tropical Diseases ◽  
Middle Income ◽  
Drug Discovery And Development ◽  
Partnership Model

Tropical diseases, including malaria and a group of infections termed neglected tropical diseases (NTDs), pose enormous threats to human health and wellbeing globally. In concert with efforts to broaden access to current treatments, it is also critical to expand research and development (R&D) of new drugs that address therapeutic gaps and concerns associated with existing medications, including emergence of resistance. Limited commercial incentives, particularly compared to products for diseases prevalent in high-income countries, have hindered many pharmaceutical companies from contributing their immense product development know-how and resources to tropical disease R&D. In this article we present WIPO Re:Search, an international initiative co-led by BIO Ventures for Global Health (BVGH) and the World Intellectual Property Organization (WIPO), as an innovative and impactful public-private partnership model that promotes cross-sector intellectual property sharing and R&D to accelerate tropical disease drug discovery and development. Importantly, WIPO Re:Search also drives progress toward the United Nations Sustainable Development Goals (SDGs). Through case studies, we illustrate how WIPO Re:Search empowers high-quality tropical disease drug discovery researchers from academic/non-profit organizations and small companies (including scientists in low- and middle-income countries) to leapfrog their R&D programs by accessing pharmaceutical industry resources that may not otherwise be available to them.

scholarly journals Neglected tropical diseases in Brazil

2009 ◽  
Vol 51 (5) ◽  
pp. 247-253 ◽  
Author(s):  
José Angelo L. Lindoso ◽  
Ana Angélica B.P. Lindoso
Keyword(s):  
Neglected Tropical Diseases ◽  
Clinical Manifestations ◽  
Northern Region ◽  
New Drugs ◽  
World Health ◽  
Tropical Diseases ◽  
The North ◽  
The World ◽  
The Status ◽  
Health Organization

Poverty is intrinsically related to the incidence of Neglected Tropical Diseases (NTDs). The main countries that have the lowest human development indices (HDI) and the highest burdens of NTDs are located in tropical and subtropical regions of the world. Among these countries is Brazil, which is ranked 70th in HDI. Nine out of the ten NTDs established by the World Health Organization (WHO) are present in Brazil. Leishmaniasis, tuberculosis, dengue fever and leprosy are present over almost the entire Brazilian territory. More than 90% of malaria cases occur in the Northern region of the country, and lymphatic filariasis and onchocerciasis occur in outbreaks in a particular region. The North and Northeast regions of Brazil have the lowest HDIs and the highest rates of NTDs. These diseases are considered neglected because there is not important investment in projects for the development of new drugs and vaccines and existing programs to control these diseases are not sufficient. Another problem related to NTDs is co-infection with HIV, which favors the occurrence of severe clinical manifestations and therapeutic failure. In this article, we describe the status of the main NTDs currently occurring in Brazil and relate them to the HDI and poverty.

Targeting pteridine reductase 1 and dihydrofolate reductase: the old is a new trend for leishmaniasis drug discovery

2019 ◽  
Vol 11 (16) ◽  
pp. 2107-2130 ◽  
Author(s):  
Gustavo Machado das Neves ◽  
Luciano P Kagami ◽  
Itamar L Gonçalves ◽  
Vera L Eifler-Lima
Keyword(s):  
Dihydrofolate Reductase ◽  
Drug Targets ◽  
Neglected Tropical Diseases ◽  
Molecular Targets ◽  
New Drugs ◽  
Tropical Diseases ◽  
The World ◽  
Leishmania Spp ◽  
Systemic Manifestations ◽  
Potential Drug Targets

Leishmaniasis is one of the major neglected tropical diseases in the world and it is considered endemic in 88 countries. This disease is transmitted by a Leishmania spp. infected sandfly and it may lead to cutaneous or systemic manifestations. The preconized treatment has low efficacy and there are cases of resistance to some drugs. Therefore, the search for new efficient molecular targets that can lead to the preparation of new drugs must be pursued. This review aims to evaluate both Leishmania enzymes PTR1 and DHFR-TS as potential drug targets, highlight their inhibitors and to discuss critically the use of chemoinformatics to elucidate interactions and propose new molecules against these enzymes.

scholarly journals The Dialogue of the Host-Parasite Relationship:Leishmaniaspp. andTrypanosoma cruziInfection

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Carlos Gustavo Vieira de Morais ◽  
Ana Karina Castro Lima ◽  
Rodrigo Terra ◽  
Rosiane Freire dos Santos ◽  
Silvia Amaral Gonçalves Da-Silva ◽  
...  
Keyword(s):  
Immune Response ◽  
Trypanosoma Cruzi ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Host Cells ◽  
Protective Response ◽  
Limited Efficacy ◽  
Causative Agents ◽  
Host Parasite ◽  
Emergence Of Resistance

The intracellular protozoaLeishmaniaspp. andTrypanosoma cruziand the causative agents of Leishmaniasis and Chagas disease, respectively, belong to the Trypanosomatidae family. Together, these two neglected tropical diseases affect approximately 25 million people worldwide. Whether the host can control the infection or develops disease depends on the complex interaction between parasite and host. Parasite surface and secreted molecules are involved in triggering specific signaling pathways essential for parasite entry and intracellular survival. The recognition of the parasite antigens by host immune cells generates a specific immune response.Leishmaniaspp. andT. cruzihave a multifaceted repertoire of strategies to evade or subvert the immune system by interfering with a range of signal transduction pathways in host cells, which causes the inhibition of the protective response and contributes to their persistence in the host. The current therapeutic strategies in leishmaniasis and trypanosomiasis are very limited. Efficacy is variable, toxicity is high, and the emergence of resistance is increasingly common. In this review, we discuss the molecular basis of the host-parasite interaction ofLeishmaniaandTrypanosoma cruziinfection and their mechanisms of subverting the immune response and how this knowledge can be used as a tool for the development of new drugs.

scholarly journals Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases

2015 ◽  
Vol 12 (104) ◽  
pp. 20141289 ◽  
Author(s):  
Kevin Williams ◽  
Elizabeth Bilsland ◽  
Andrew Sparkes ◽  
Wayne Aubrey ◽  
Michael Young ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Boolean Functions ◽  
Neglected Tropical Diseases ◽  
Quantitative Structure Activity Relationship ◽  
New Drugs ◽  
Automation System ◽  
Tropical Diseases ◽  
Standard Drug ◽  
Anti Cancer ◽  
Lead Generation

There is an urgent need to make drug discovery cheaper and faster. This will enable the development of treatments for diseases currently neglected for economic reasons, such as tropical and orphan diseases, and generally increase the supply of new drugs. Here, we report the Robot Scientist ‘Eve’ designed to make drug discovery more economical. A Robot Scientist is a laboratory automation system that uses artificial intelligence (AI) techniques to discover scientific knowledge through cycles of experimentation. Eve integrates and automates library-screening, hit-confirmation, and lead generation through cycles of quantitative structure activity relationship learning and testing. Using econometric modelling we demonstrate that the use of AI to select compounds economically outperforms standard drug screening. For further efficiency Eve uses a standardized form of assay to compute Boolean functions of compound properties. These assays can be quickly and cheaply engineered using synthetic biology, enabling more targets to be assayed for a given budget. Eve has repositioned several drugs against specific targets in parasites that cause tropical diseases. One validated discovery is that the anti-cancer compound TNP-470 is a potent inhibitor of dihydrofolate reductase from the malaria-causing parasite Plasmodium vivax .

scholarly journals Impaired Cytotoxic Response in PBMCs From Patients With COVID-19 Admitted to the ICU: Biomarkers to Predict Disease Severity

2021 ◽  
Vol 12 ◽  
Author(s):  
Lorena Vigón ◽  
Daniel Fuertes ◽  
Javier García-Pérez ◽  
Montserrat Torres ◽  
Sara Rodríguez-Mora ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Invasive Mechanical Ventilation ◽  
Cell Subpopulation ◽  
Target Cells ◽  
Immunological Parameters ◽  
Cytotoxic Response ◽  
Infected Cells ◽  
Novel Coronavirus ◽  
Cellular Immune

Infection by novel coronavirus SARS-CoV-2 causes different presentations of COVID-19 and some patients may progress to a critical, fatal form of the disease that requires their admission to ICU and invasive mechanical ventilation. In order to predict in advance which patients could be more susceptible to develop a critical form of COVID-19, it is essential to define the most adequate biomarkers. In this study, we analyzed several parameters related to the cellular immune response in blood samples from 109 patients with different presentations of COVID-19 who were recruited in Hospitals and Primary Healthcare Centers in Madrid, Spain, during the first pandemic peak between April and June 2020. Hospitalized patients with the most severe forms of COVID-19 showed a potent inflammatory response that was not translated into an efficient immune response. Despite the high levels of effector cytotoxic cell populations such as NK, NKT and CD8+ T cells, they displayed immune exhaustion markers and poor cytotoxic functionality against target cells infected with pseudotyped SARS-CoV-2 or cells lacking MHC class I molecules. Moreover, patients with critical COVID-19 showed low levels of the highly cytotoxic TCRγδ+ CD8+ T cell subpopulation. Conversely, CD4 count was greatly reduced in association to high levels of Tregs, low plasma IL-2 and impaired Th1 differentiation. The relative importance of these immunological parameters to predict COVID-19 severity was analyzed by Random Forest algorithm and we concluded that the most important features were related to an efficient cytotoxic response. Therefore, efforts to fight against SARS-CoV-2 infection should be focused not only to decrease the disproportionate inflammatory response, but also to elicit an efficient cytotoxic response against the infected cells and to reduce viral replication.

scholarly journals PREDICTORS OF EFFECTIVE USE OF T CELL MIMETICS IN IMMUNE AND ENDOCRINE DISORDERS TREATMENT

2019 ◽  
Vol 19 (1S) ◽  
pp. 176-178
Author(s):  
D S Luybimov ◽  
A N Britanov
Keyword(s):  
Immune Response ◽  
Bacterial Infections ◽  
Acute Bronchitis ◽  
Acute Stage ◽  
Endocrine Disorders ◽  
Clinical Markers ◽  
Phagocytic Capacity ◽  
Humoral Immune ◽  
Neurohumoral Regulation ◽  
Cellular Immune

98 infants with acute bronchitis aged 3-36 months showed general basic adaptive response on the acute stage: depression of cellular immune response, active humoral immune response, CIC increase and enhanced phagocytic capacity of neutrophils. ACTH and TSH levels were elevated against depletion of cortisol and triiodothyronine levels. Clinical markers together with immune and endocrine predictive markers of the disease severity, character of complications and comorbidity were revealed. Thymogen is indicated for treatment in case of prevailing of hyperergic disorders both in the central core of neurohumoral regulation and the intra-immune - IgA increase. Thymaline proves effective in hyperergia treatment - thymomegaly with low IgA and cortisol levels along with pre-existing bacterial infections.

scholarly journals Systematic study of triazolyl sterols for the development of new drugs against parasitic Neglected Tropical Diseases.

2021 ◽  
Author(s):  
Exequiel Porta ◽  
Shane Wilkinson ◽  
María Sol Ballari ◽  
Babu Tekwani ◽  
Guillermo Labadie
Keyword(s):  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
Selectivity Index ◽  
New Drugs ◽  
Tropical Diseases ◽  
Antiparasitic Activity ◽  
Nanomolar Concentration ◽  
Stereocontrolled Synthesis ◽  
Etiological Agents ◽  
Excellent Selectivity

A series of thirty 1,2,3-triazolylsterols were prepared by a stereocontrolled synthesis and inspired by azasterols with proven antiparasitic activity. Ten of these compounds constitute chimeras/hybrids of AZA and 1,2,3-triazolyl azasterols. The entire library was assayed against the etiological agents of the parasites responsible of kinetoplastid diseases (L. donovani, T. cruzi and T. brucei). Several of the compounds were active at submicromolar/nanomolar concentration with excellent selectivity index, when compared to their activity in mammalian cells. Studies of the physicochemical properties in silico were conducted to rationalize the activities.

Collaborations aim to develop new drugs for neglected tropical diseases

BMJ ◽  
2009 ◽  
Vol 338 (jun29 2) ◽  
pp. b2638-b2638 ◽  
Author(s):  
J. H. Tanne
Keyword(s):  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Tropical Diseases
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