Drug Screening for Discovery of Broad-spectrum Agents for Soil-transmitted Nematodes

Elfawal, Mostafa A.; Savinov, Sergey N.; Aroian, Raffi V.

doi:10.1038/s41598-019-48720-1

Cited by 38 publications

(49 citation statements)

References 90 publications

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“…To date, there has been no drug developed specifically for human GINs. All drugs used for human GIN treatment came from drugs developed for veterinary targets (64). Furthermore, the availability of current drugs for human MDA relies upon off-patent drugs that are donated (22).…”

Section: Discussionmentioning

confidence: 99%

Recombinant Paraprobiotics as a New Paradigm for Treating Gastrointestinal Nematode Parasites of Humans

Abraham

Gazzola

et al. 2020

Preprint

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Gastrointestinal nematodes (GINs) of humans, e.g., hookworms, negatively impact childhood growth, cognition, nutrition, educational attainment, income, productivity, and pregnancy. Hundreds of millions of people are targeted with mass drug administration (MDA) of donated benzimidazole (BZ) anthelmintics. However, BZ efficacy against GINs is suboptimal, and reduced/low efficacy has been seen. Developing an anthelmintic for human MDA is daunting: it must be safe, effective, inexpensive, stable without a cold chain, and massively scalable. Bacillus thuringiensis (Bt) crystal protein 5B (Cry5B) has anthelmintic properties that could fill this void. Here we develop an API (Active Pharmaceutical Ingredient) form of Bt Cry5B compatible with MDA. We expressed Cry5B in asporogenous Bt during vegetative phase, forming cytosolic crystals. These Bacteria with Cytosolic Crystals (BaCC) were rendered inviable (inactivated BaCC or IBaCC) with food-grade essential oils. IBaCC potency was validated in vitro against nematodes. IBaCC was also potent in vivo against human hookworm infections in hamsters. IBaCC production was successfully scaled to 350 liters at a contract manufacturing facility. A simple fit-for-purpose formulation to protect against stomach digestion and powdered IBaCC were successfully made and used against GINS in hamsters and mice. A pilot histopathology study and blood chemistry workup showed that five daily consecutive doses of 200 mg/kg Cry5B IBaCC (the curative single dose is 40 mg/kg) was non-toxic and completely safe. IBaCC is a safe, inexpensive, highly effective, easy-to-manufacture, and scalable anthelmintic that is practical for MDA and represents a new paradigm for treating human GINs.

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Section: Discussionmentioning

confidence: 99%

Recombinant Paraprobiotics as a New Paradigm for Treating Gastrointestinal Nematode Parasites of Humans

Abraham

Gazzola

et al. 2020

Preprint

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“…Aroian and colleagues [98], in line with the work of Burns et al [94], counsel caution on relying on data from C. elegans alone, which makes perfect sense as it is never the primary target organism. They screened a compound library against both adult and free-living larval stages (egg to L3i larval development assay, E2L) of the human hookworm parasite Ancylostoma ceylanicum and against C. elegans.…”

Section: Elegans As a Model Nematodementioning

confidence: 99%

“…Compounds with anthelmintic activity identified by a combination of screening against Ancylostoma ceylanicum, C. elegans, and T. muris[98].…”

mentioning

confidence: 99%

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

Partridge¹,

Forman²,

Bataille³

et al. 2020

Beilstein J. Org. Chem.

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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.

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“…Most studies use only a single target organism, which in many cases is not a parasite (i.e., C. elegans). In vitro evidence of activity on a suitable parasite is probably essential for progressing a compound for further development, although well-documented anthelmintic traditional use, in conjunction with C. elegans activity, gives more confidence that the activity will persist on parasites, compared to compounds emerging from a screen of a chemical library [114,115].…”

Section: Spectrummentioning

confidence: 99%

Plant-Based Natural Products for the Discovery and Development of Novel Anthelmintics against Nematodes

2020

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Intestinal parasitic nematodes infect approximately two billion people worldwide. In the absence of vaccines for human intestinal nematodes, control of infections currently relies mainly on chemotherapy, but resistance is an increasing problem. Thus, there is an urgent need for the discovery and development of new anthelmintic drugs, especially ones with novel mechanisms of action. Medicinal plants hold great promise as a source of effective treatments, including anthelmintic therapy. They have been used traditionally for centuries and are mostly safe (if not, their toxicity is well-known). However, in most medicinal plants the compounds active against nematodes have not been identified thus far. The free-living nematode C. elegans was demonstrated to be an excellent model system for the discovery of new anthelmintics and for characterizing their mechanism of action or resistance. The compounds discussed in this review are of botanical origin and were published since 2002. Most of them need further studies of their toxicity, mechanisms and structure-activity relationship to assess more fully their potential as drugs.

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Drug Screening for Discovery of Broad-spectrum Agents for Soil-transmitted Nematodes

Cited by 38 publications

References 90 publications

Recombinant Paraprobiotics as a New Paradigm for Treating Gastrointestinal Nematode Parasites of Humans

Recombinant Paraprobiotics as a New Paradigm for Treating Gastrointestinal Nematode Parasites of Humans

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

Plant-Based Natural Products for the Discovery and Development of Novel Anthelmintics against Nematodes

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