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Related Experiment Video

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Repurposing Infectious Disease Hits as Anti-Cryptosporidium Leads.

Matthew A Hulverson1, Ryan Choi1, Molly C McCloskey1

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ACS Infectious Diseases
|March 19, 2021
PubMed
Summary

A novel imidazole-pyrimidine compound shows promise for treating Cryptosporidium infections, demonstrating significant efficacy in a mouse model. This discovery offers a potential new therapeutic avenue for cryptosporidiosis, especially in vulnerable populations.

Keywords:
CryptosporidiumN-carbamoylazolecalcium dependent protein kinase 1cryptosporidiosiscyclic GMP-dependent protein kinaseimidazole-pyrimidine

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Area of Science:

  • Drug discovery and development
  • Infectious diseases
  • Parasitology

Background:

  • Cryptosporidium infections pose a significant health burden, particularly in young children and immunocompromised individuals.
  • Existing treatments for cryptosporidiosis are limited, necessitating the development of new therapeutic agents.
  • The Tres-Cantos GSK compound library was screened for compounds with activity against Cryptosporidium parvum.

Purpose of the Study:

  • To identify and evaluate bioactive compounds for repurposing as treatments against Cryptosporidium parvum.
  • To discover novel drug candidates for cryptosporidiosis with favorable safety and pharmacokinetic profiles.

Main Methods:

  • Screening of the Tres-Cantos GSK library for compounds inhibiting Cryptosporidium parvum growth.
  • Iterative removal of toxic compounds and screening of related structural analogs.
  • Evaluation of promising compounds in a mouse model of Cryptosporidium parvum infection.
  • Assessment of the mechanism of action, including inhibition of calcium-dependent protein kinase 1 (CDPK1).

Main Results:

  • Nineteen compounds from nine structural clusters were identified with activity against Cryptosporidium parvum.
  • One imidazole-pyrimidine compound demonstrated significant clearance of infection in a mouse model at doses as low as 30 mg/kg daily.
  • The lead imidazole-pyrimidine compound exhibited favorable safety and pharmacokinetic properties.
  • The compound potently inhibited Cryptosporidium parvum CDPK1 with a 50% inhibitory concentration (IC50) of 2 nM.

Conclusions:

  • An imidazole-pyrimidine compound represents a promising lead for the development of new Cryptosporidium therapeutics.
  • Further investigation of this compound and related analogs is warranted for cryptosporidiosis treatment.
  • Targeting Cryptosporidium parvum CDPK1 is a viable strategy for developing novel anti-parasitic drugs.