scholarly journals Anthelmintic drug discovery: target identification, screening methods and the role of open science

2020 ◽  
Vol 16 ◽  
pp. 1203-1224 ◽  
Author(s):  
Frederick A Partridge ◽  
Ruth Forman ◽  
Carole J R Bataille ◽  
Graham M Wynne ◽  
Marina Nick ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Neglected Tropical Diseases ◽  
Open Science ◽  
New Drugs ◽  
World Health ◽  
Neglected Diseases ◽  
Screening Methods ◽  
Screening Programs ◽  
Anthelmintic Drug ◽  
Compound Screening

Helminths, including cestodes, nematodes and trematodes, are a huge global health burden, infecting hundreds of millions of people. In many cases, existing drugs such as benzimidazoles, diethylcarbamazine, ivermectin and praziquantel are insufficiently efficacious, contraindicated in some populations, or at risk of the development of resistance, thereby impeding progress towards World Health Organization goals to control or eliminate these neglected tropical diseases. However, there has been limited recent progress in developing new drugs for these diseases due to lack of commercial attractiveness, leading to the introduction of novel, more efficient models for drug innovation that attempt to reduce the cost of research and development. Open science aims to achieve this by encouraging collaboration and the sharing of data and resources between organisations. In this review we discuss how open science has been applied to anthelmintic drug discovery. Open resources, including genomic information from many parasites, are enabling the identification of targets for new antiparasitic agents. Phenotypic screening remains important, and there has been much progress in open-source systems for compound screening with parasites, including motility assays but also high content assays with more detailed investigation of helminth physiology. Distributed open science compound screening programs, such as the Medicines for Malaria Venture Pathogen Box, have been successful at facilitating screening in diverse assays against many different parasite pathogens and models. Of the compounds identified so far in these screens, tolfenpyrad, a repurposed insecticide, shows significant promise and there has been much progress in creating more potent and selective derivatives. This work exemplifies how open science approaches can catalyse drug discovery against neglected diseases.

scholarly journals Potentials of marine natural products against malaria, leishmaniasis, and trypanosomiasis parasites: a review of recent articles

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Justus Amuche Nweze ◽  
Florence N. Mbaoji ◽  
Yan-Ming Li ◽  
Li-Yan Yang ◽  
Shu-Shi Huang ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Marine Natural Products ◽  
Neglected Tropical Diseases ◽  
Marine Organisms ◽  
New Drugs ◽  
Screening Methods ◽  
Pharmaceutical Industries

Abstract Background Malaria and neglected communicable protozoa parasitic diseases, such as leishmaniasis, and trypanosomiasis, are among the otherwise called diseases for neglected communities, which are habitual in underprivileged populations in developing tropical and subtropical regions of Africa, Asia, and the Americas. Some of the currently available therapeutic drugs have some limitations such as toxicity and questionable efficacy and long treatment period, which have encouraged resistance. These have prompted many researchers to focus on finding new drugs that are safe, effective, and affordable from marine environments. The aim of this review was to show the diversity, structural scaffolds, in-vitro or in-vivo efficacy, and recent progress made in the discovery/isolation of marine natural products (MNPs) with potent bioactivity against malaria, leishmaniasis, and trypanosomiasis. Main text We searched PubMed and Google scholar using Boolean Operators (AND, OR, and NOT) and the combination of related terms for articles on marine natural products (MNPs) discovery published only in English language from January 2016 to June 2020. Twenty nine articles reported the isolation, identification and antiparasitic activity of the isolated compounds from marine environment. A total of 125 compounds were reported to have been isolated, out of which 45 were newly isolated compounds. These compounds were all isolated from bacteria, a fungus, sponges, algae, a bryozoan, cnidarians and soft corals. In recent years, great progress is being made on anti-malarial drug discovery from marine organisms with the isolation of these potent compounds. Comparably, some of these promising antikinetoplastid MNPs have potency better or similar to conventional drugs and could be developed as both antileishmanial and antitrypanosomal drugs. However, very few of these MNPs have a pharmaceutical destiny due to lack of the following: sustainable production of the bioactive compounds, standard efficient screening methods, knowledge of the mechanism of action, partnerships between researchers and pharmaceutical industries. Conclusions It is crystal clear that marine organisms are a rich source of antiparasitic compounds, such as alkaloids, terpenoids, peptides, polyketides, terpene, coumarins, steroids, fatty acid derivatives, and lactones. The current and future technological innovation in natural products drug discovery will bolster the drug armamentarium for malaria and neglected tropical diseases.

scholarly journals Drug repurposing: cost effectiveness and impact on emerging and neglected diseases

2020 ◽  
Vol 16 (1) ◽  
pp. 3-17
Author(s):  
Matthew Obaineh Ojezele ◽  
Joseph Mordi ◽  
Emmanuel Adesola Adedapo
Keyword(s):  
Drug Discovery ◽  
Neglected Tropical Diseases ◽  
Drug Repurposing ◽  
Orphan Drugs ◽  
New Drugs ◽  
Neglected Diseases ◽  
Developmental Cycle ◽  
Technological Advancement ◽  
Therapeutic Uses ◽  
Human Pollution

Historically, pressure on nature brought about by ever-increasing human pollution and technological advancement culminate in emergence and re- emergence of infectious and non-infectious diseases; necessitating medications and drug discovery and development. The emergence of resistantmicroorganisms and the emergence of new infections disease conditions necessitate the production of entirely new drugs or modification of the existing ones to increase their efficacy. The development of novel medications is a very long and expensive process. There is a significant decrease observed in the number of new drugs approved for clinical use in recent years showing inconsistency in the face of scientific advances and research and development investment. Regardless of high investment and enormous contributions, very few molecules showed promising results. However, finding novel indications for existing drugs can be a useful method of reducing the developmental cycle of drugs. Repositioning (also called repurposing) has been described as the practice of developing new therapeutic uses for drugs, abandoned or drugs in development process, other than the initially intended or approved uses, except for the circumstances in which the novel use is comparable to the original indication with dissimilar pharmacological targets. This review aimed at looking into some of the available methods in drug repurposing. Key words: Drug discovery; Drug repurposing; Machine learning; Neglected Tropical diseases; Orphan 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 Accelerating Drug Discovery Efforts for Trypanosomatidic Infections Using an Integrated Transnational Academic Drug Discovery Platform

2019 ◽  
Vol 24 (3) ◽  
pp. 346-361 ◽  
Author(s):  
Carolina B. Moraes ◽  
Gesa Witt ◽  
Maria Kuzikov ◽  
Bernhard Ellinger ◽  
Theodora Calogeropoulou ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Trypanosoma Brucei ◽  
Value Chain ◽  
Neglected Tropical Diseases ◽  
World Health ◽  
Synthetic Compound ◽  
Antiparasitic Activity ◽  
Compound Libraries ◽  
Health Organization

According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion–toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 ( TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain.

scholarly journals Susceptibility Testing of Medically Important Parasites

2017 ◽  
Vol 30 (3) ◽  
pp. 647-669 ◽  
Author(s):  
Abebe Genetu Bayih ◽  
Anjan Debnath ◽  
Edward Mitre ◽  
Christopher D. Huston ◽  
Benoît Laleu ◽  
...  
Keyword(s):  
Susceptibility Testing ◽  
Neglected Tropical Diseases ◽  
State Of The Art ◽  
Life Cycles ◽  
Point Of View ◽  
New Drugs ◽  
Screening Methods ◽  
Laboratory Methods ◽  
Antiparasitic Agents

SUMMARY In the last 2 decades, renewed attention to neglected tropical diseases (NTDs) has spurred the development of antiparasitic agents, especially in light of emerging drug resistance. The need for new drugs has required in vitro screening methods using parasite culture. Furthermore, clinical laboratories sought to correlate in vitro susceptibility methods with treatment outcomes, most notably with malaria. Parasites with their various life cycles present greater complexity than bacteria, for which standardized susceptibility methods exist. This review catalogs the state-of-the-art methodologies used to evaluate the effects of drugs on key human parasites from the point of view of drug discovery as well as the need for laboratory methods that correlate with clinical outcomes.

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.

scholarly journals Capsaicin inhibits arginine kinase and exerts anti-Trypanosoma cruzi activity

2020 ◽  
Author(s):  
Edward A. Valera-Vera ◽  
Chantal Reigada ◽  
Melisa Sayé ◽  
Fabio A. Digirolamo ◽  
Mariana R. Miranda ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Stress Responses ◽  
Mammalian Cells ◽  
Arginine Kinase ◽  
Chronic Phase ◽  
New Drugs ◽  
World Health ◽  
Neglected Diseases ◽  
Health Organization

ABSTRACTTrypanosoma cruzi is the causative agent of Chagas disease, considered within the list of twenty neglected diseases according to the World Health Organization. There are only two therapeutic drugs for Chagas disease, both of them unsuitable for the chronic phase, therefore the development of new drugs is a priority.T. cruzi arginine kinase (TcAK) is a promising drug target since it is absent in humans and it is involved in cellular stress responses. In a previous study from our laboratory, possible TcAK inhibitors were identified through computer simulations, resulting in the best-scoring compounds cyanidin derivatives and capsaicin. Considering these results, in this work we evaluate the effect of capsaicin on TcAK activity and its trypanocidal effect. Although capsaicin produced a weak inhibition on the recombinant TcAK activity (IC50 ≈ 800 µM), it had a strong trypanocidal effect on epimastigotes and trypomastigotes (IC50 = 6.26 µM and 0.26 µM, respectively) being 20-fold more active on trypomastigotes than mammalian cells. Epimastigotes that overexpress TcAK were 37% more resistant to capsaicin than wild type parasites, suggesting that trypanocidal activity could be due, in part, to the enzyme inhibition. However, the difference between the concentrations at which the enzyme is inhibited and the parasite death is caused implies the presence of other targets. In this sense, the prohibitin-2 and calmodulin were identified as other possible capsaicin targets. Capsaicin is a strong and selective trypanocidal agent active in nanomolar concentrations, with an IC50 57-fold lower than benznidazole, the drug currently used for treating Chagas disease.

scholarly journals Development of emodepside as a possible adulticidal treatment for human onchocerciasis—The fruit of a successful industrial–academic collaboration

2021 ◽  
Vol 17 (7) ◽  
pp. e1009682
Author(s):  
Jürgen Krücken ◽  
Lindy Holden-Dye ◽  
Jennifer Keiser ◽  
Roger K. Prichard ◽  
Simon Townson ◽  
...  
Keyword(s):  
Drug Development ◽  
Broad Spectrum ◽  
Neglected Tropical Diseases ◽  
Current Knowledge ◽  
Animal Health ◽  
World Health ◽  
Parasitic Nematodes ◽  
Term Therapy ◽  
Neglected Diseases ◽  
Phase I Clinical Trials

Current mass drug administration (MDA) programs for the treatment of human river blindness (onchocerciasis) caused by the filarial worm Onchocerca volvulus rely on ivermectin, an anthelmintic originally developed for animal health. These treatments are primarily directed against migrating microfilariae and also suppress fecundity for several months, but fail to eliminate adult O. volvulus. Therefore, elimination programs need time frames of decades, well exceeding the life span of adult worms. The situation is worsened by decreased ivermectin efficacy after long-term therapy. To improve treatment options against onchocerciasis, a drug development candidate should ideally kill or irreversibly sterilize adult worms. Emodepside is a broad-spectrum anthelmintic used for the treatment of parasitic nematodes in cats and dogs (Profender and Procox). Our current knowledge of the pharmacology of emodepside is the result of more than 2 decades of intensive collaborative research between academia and the pharmaceutical industry. Emodepside has a novel mode of action with a broad spectrum of activity, including against extraintestinal nematode stages such as migrating larvae or macrofilariae. Therefore, emodepside is considered to be among the most promising candidates for evaluation as an adulticide treatment against onchocerciasis. Consequently, in 2014, Bayer and the Drugs for Neglected Diseases initiative (DNDi) started a collaboration to develop emodepside for the treatment of patients suffering from the disease. Macrofilaricidal activity has been demonstrated in various models, including Onchocerca ochengi in cattle, the parasite most closely related to O. volvulus. Emodepside has now successfully passed Phase I clinical trials, and a Phase II study is planned. This Bayer–DNDi partnership is an outstanding example of “One World Health,” in which experience gained in veterinary science and drug development is translated to human health and leads to improved tools to combat neglected tropical diseases (NTDs) and shorten development pathways and timelines in an otherwise neglected area.

scholarly journals New global targets for NTDs in the WHO roadmap 2021–2030

2021 ◽  
Vol 15 (5) ◽  
pp. e0009373
Author(s):  
Adriano Casulli
Keyword(s):  
Prevention And Control ◽  
Neglected Tropical Diseases ◽  
World Health ◽  
Neglected Diseases ◽  
Tropical Diseases ◽  
Future Prospects ◽  
The World ◽  
Health Organization ◽  
And Control ◽  
Second World

The second World Neglected Tropical Diseases (NTDs) Day was celebrated on 30 January 2021. To mark the occasion, the World Health Organization (WHO) launched its roadmap for NTDs for the period 2021 to 2030, which is aimed at increasing prevention and control of these too-long neglected diseases. Described here is a global overview on past achievements, current challenges, and future prospects for the WHO NTDs roadmap 2021–2030.

First Example of Antiparasitic Activity Influenced by Thermochromism: Leishmanicidal Evaluation of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine Metal Complexes

2020 ◽  
Vol 16 (3) ◽  
pp. 422-430 ◽  
Author(s):  
José M. Méndez-Arriaga ◽  
Itziar Oyarzabal ◽  
Álvaro Martín-Montes ◽  
Judith García-Rodríguez ◽  
Miguel Quirós ◽  
...  
Keyword(s):  
Physical Properties ◽  
Metal Complexes ◽  
New Drugs ◽  
Host Cells ◽  
World Health ◽  
Neglected Diseases ◽  
Leishmania Spp ◽  
Different Strains ◽  
Health Organization

Background: The World Health Organization catalogues illnesses such as Leishmaniasis as neglected diseases, due to low investment in new drugs to fight them. The search of novel and non-side effects anti-parasitic compounds is one of the urgent needs for the Third World. The use of triazolopyrimidines and their metallic complexes has demonstrated hopeful results in this field. Objective: This work studies the antiparasitic efficacy of a series of 5,7-dimethyl-1,2,4- triazolo[1,5-a]pyrimidine first row transition metal complexes against three leishmania spp. strains. Methods: The in vitro antiproliferation of promastigote forms of different strains of leishmania spp. (L. infantum, L. braziliensis and L donovani) and the cytotoxicity in macrophage host cells are reported here. The antiparasitic assays have been complemented with enzymatic tests to elucidate the mechanisms of action. New crystal structure description, thermal analysis, magnetic susceptibility and magnetization experiments have also been carried out in order to present a whole characterization of the studied compounds and interesting physical properties besides the biological tests. Results: The results of antiproliferation screening and cytotoxicity show great antiparasitic efficacy in the studied complexes. The superoxide dismutase enzymatic assays exhibit a different behaviour according to the thermochromic triazolopyrimidine form tested. Conclusion: Antiproliferative assays and enzymatic tests corroborate the synergetic leishmanicidal effect present in coordination triazolopyrimidine complexes. The changes in coordination sphere derived from thermochromism affect the physical properties as well as the biological efficacy.

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