2. Academic Validation
  3. Cryptosporidium lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy

Cryptosporidium lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy

  • Sci Transl Med. 2024 Oct 23;16(770):eadm8631. doi: 10.1126/scitranslmed.adm8631.
Nicola Caldwell 1,  Caroline Peet 1,  Peter Miller 2,  Beatrice L Colon 1,  Malcolm G Taylor 1,  Mattia Cocco 1,  Alice Dawson 1,  Iva Lukac 1,  Jose E Teixeira 2,  Lee Robinson 1,  Laura Frame 1,  Simona Seizova 1,  Sebastian Damerow 1,  Fabio Tamaki 1,  John Post 1,  Jennifer Riley 1,  Nicole Mutter 1,  Jack C Hanna 1,  Liam Ferguson 1,  Xiao Hu 1,  Michele Tinti 1,  Barbara Forte 1,  Neil R Norcross 1,  Peter S Campbell 1,  Nina Svensen 1,  Flora C Caldwell 1,  Chimed Jansen 1,  Vincent Postis 1,  Kevin D Read 1,  Christopher D Huston 2,  Ian H Gilbert 1,  Beatriz Baragaña 1,  Mattie C Pawlowic 1
Affiliations

Affiliations

  • 1 Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
  • 2 Department of Medicine, University of Vermont, Larner College of Medicine, Burlington, VT 05401, USA.
PMID: 39441903 DOI: 10.1126/scitranslmed.adm8631
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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