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Cryptosporidium lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to
Nicola Caldwell1, Caroline Peet1, Peter Miller2
1Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Insights
New drug development for cryptosporidiosis, a leading cause of death in malnourished children, is crucial. This study identified key compound properties and promising drug candidates (DDD489 and DDD508) for treating this parasitic infection.
Area of Science:
- Infectious Diseases
- Drug Discovery
- Parasitology
Background:
- Cryptosporidiosis is a significant diarrheal disease, particularly deadly in malnourished children globally.
- Current treatment, nitazoxanide, shows limited efficacy in this vulnerable population, highlighting an urgent need for new therapeutics.
- Drug development for cryptosporidiosis is impeded by insufficient understanding of essential compound properties for gastrointestinal infection treatment.
Purpose of the Study:
- To identify optimal physicochemical and pharmacokinetic properties for anti-cryptosporidial drug efficacy.
- To establish predictive in vitro criteria for guiding the optimization of novel anti-cryptosporidial agents.
- To discover potent drug candidates for cryptosporidiosis treatment.
Main Methods:
- Profiling a diverse set of lysyl-tRNA synthetase inhibitors.
- Evaluating compound efficacy in a chronic mouse model of cryptosporidiosis.
- Assessing parasite reduction in immunocompromised mouse and calf models.
Main Results:
- Efficacy in vivo is linked to a balance between compound solubility and permeability.
- Established in vitro criteria for solubility and permeability predict in vivo efficacy.
- Two distinct compounds, DDD489 and DDD508, demonstrated superior efficacy and significant parasite reduction.
Conclusions:
- Optimizing solubility and permeability is critical for developing effective anti-cryptosporidial drugs.
- DDD489 and DDD508 show significant promise and are selected for preclinical safety studies.
- This research expands the pipeline for treating neglected infectious diseases like cryptosporidiosis.
Abstract:
Cryptosporidiosis is a diarrheal disease caused by infection with Cryptosporidium spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population. Additional safe therapeutics are urgently required to tackle this unmet medical need. However, the development of anti-cryptosporidial drugs is hindered by a lack of understanding of the optimal compound properties required to treat this gastrointestinal infection. To address this knowledge gap, a diverse set of potent lysyl-tRNA synthetase inhibitors was profiled to identify optimal physicochemical and pharmacokinetic properties required for efficacy in a chronic mouse model of infection. The results from this comprehensive study illustrated the importance of balancing solubility and permeability to achieve efficacy in vivo. Our results establish in vitro criteria for solubility and permeability that are predictive of compound efficacy in vivo to guide the optimization of anti-cryptosporidial drugs. Two compounds from chemically distinct series (DDD489 and DDD508) were identified as demonstrating superior efficacy and prioritized for further evaluation. Both compounds achieved marked parasite reduction in immunocompromised mouse models and a disease-relevant calf model of infection. On the basis of these promising data, these compounds have been selected for progression to preclinical safety studies, expanding the portfolio of potential treatments for this neglected infectious disease.
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