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Addressing the most neglected diseases through an open research model: The discovery of fenarimols as novel drug candidates for eumycetoma.

ABSTRACT: Eumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungus Madurella mycetomatis. A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease. In this study, we screened 800 diverse drug-like molecules and identified 215 molecules that were active in vitro. Minimal inhibitory concentrations were determined for the 13 most active compounds. One of the most potent compounds, a fenarimol analogue for which a large analogue library is available, led to the screening of an additional 35 compounds for their in vitro activity against M. mycetomatis hyphae, rendering four further hit compounds. To assess the in vivo potency of these hit compounds, a Galleria mellonella larvae model infected with M. mycetomatis was used. Several of the compounds identified in vitro demonstrated promising efficacy in vivo in terms of prolonged larval survival and/or reduced fungal burden. The results presented in this paper are the starting point of an Open Source Mycetoma (MycetOS) approach in which members of the global scientific community are invited to participate and contribute as equal partners. We hope that this initiative, coupled with the promising new hits we have reported, will lead to progress in drug discovery for this most neglected of neglected tropical diseases.

SUBMITTER: Lim W

PROVIDER: S-EPMC5940239 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Addressing the most neglected diseases through an open research model: The discovery of fenarimols as novel drug candidates for eumycetoma.

Lim Wilson W Melse Youri Y Konings Mickey M Phat Duong Hung H Eadie Kimberly K Laleu Benoît B Perry Benjamin B Todd Matthew H MH Ioset Jean-Robert JR van de Sande Wendy W J WWJ

PLoS neglected tropical diseases 20180426 4

Eumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungus Madurella mycetomatis. A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease. In this study, we screened 800 diverse drug-like molecules and identified 215 molecules that were active in vitro. Minimal inhibitory concentratio ...[more]

PMID: 29698504

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Project description:A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

Project description:BackgroundThe World Health Organization's (WHO) Neglected Tropical Disease (NTD) Road Map for 2021-2030 was recently endorsed by all member states at the World Health Assembly in November 2020. Although only 3 of the 20 NTDs are endemic in Canada (i.e., echinococcosis, rabies, and scabies), the Canadian research community has contributed to advancing the knowledge base of all 20 NTDs. Previous research comprehensively detailed Canadian research on 11 NTDs between 1950 and 2010 using a network analysis approach. The specific objective of the present analysis was to update the publication record over the last decade (2010-2019) to include all 20 NTDs.Materials and methodsA bibliometric analysis was conducted in Scopus and Web of Science databases (for English or French articles published between January 1, 2010 and December 31, 2019) using appropriate search terms for each of the 20 NTDs and where at least 1 of the authors had a Canadian institution address. A 21st search was added to include publications including multiple NTDs or a discussion of NTDs in general. Following assessment of inclusion and exclusion criteria, 2 reviewers independently screened all abstracts, with discordant observations rereviewed to arrive at an agreement. Duplicates were removed.ResultsA total of 1,790 publications were retrieved (1,738 with a disease-specific NTD focus and 52 with a general NTD focus, resulting in 1,659 unique publications), giving an average of over 160 articles per year. Over 80% were classified as full-length research articles. The top 3 journals in terms of frequency were PLOS Neglected Tropical Diseases, PLOS ONE, and the American Journal of Tropical Medicine and Hygiene. Authors' institutions were from all Canadian provinces. While all 20 NTDs were addressed in these publications, the 5 most commonly studied were leishmaniasis, dengue fever and chikungunya, Chagas disease, soil-transmitted helminthiases, and rabies.ConclusionsCanadian researchers across the country have contributed to the evidence base of all 20 NTDs, publishing an average of over 160 publications per year between 2010 and 2019. As WHO NTD Road Map 2021-2030 rolls out globally, the Canadian research community, in collaboration with its partners and in solidarity with people living in vulnerable circumstances in endemic regions worldwide, is well positioned to meet future research challenges so that the goal of eliminating the disease burden attributable to NTDs can be achieved.

Project description:BackgroundNeglected tropical diseases (NTDs) are closely related to poverty and affect over a billion people in developing countries. The unmet treatment needs cause high mortality and disability thereby imposing a huge burden with severe social and economic consequences. Although coordinated by the World Health Organization, various philanthropic organizations, national governments and the pharmaceutical industry have been making efforts in improving the situation, the control of NTDs is still inadequate and extremely difficult today. The lack of safe, effective and affordable medicines is a key contributing factor. This paper reviews the recent advances and some of the challenges that we are facing in the fight against NTDs.Main bodyIn recent years, a number of innovations have demonstrated propensity to promote drug discovery and development for NTDs. Implementation of multilateral collaborations leads to continued efforts and plays a crucial role in drug discovery. Proactive approaches and advanced technologies are urgently needed in drug innovation for NTDs. However, the control and elimination of NTDs remain a formidable task as it requires persistent international cooperation to make sustainable progresses for a long period of time. Some currently employed strategies were proposed and verified to be successful, which involve both mechanisms of 'Push' which aims at cutting the cost of research and development for industry and 'Pull' which aims at increasing market attractiveness. Coupled to this effort should be the exercise of shared responsibility globally to reduce risks, overcome obstacles and maximize benefits. Since NTDs are closely associated with poverty, it is absolutely essential that the stakeholders take concerted and long-term measures to meet multifaceted challenges by alleviating extreme poverty, strengthening social intervention, adapting climate changes, providing effective monitoring and ensuring timely delivery.ConclusionsThe ongoing endeavor at the global scale will ultimately benefit the patients, the countries they are living and, hopefully, the manufacturers who provide new preventive, diagnostic and therapeutic products.

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Addressing the most neglected diseases through an open research model: The discovery of fenarimols as novel drug candidates for eumycetoma.

Publications

Addressing the most neglected diseases through an open research model: The discovery of fenarimols as novel drug candidates for eumycetoma.

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