Small Molecule Inhibitors of Metabolic Enzymes Repurposed as a New Class of Anthelmintics

Rahul Tyagi, Amarendar Reddy Maddirala, Mostafa Elfawal, Chelsea Fischer, Christina A. Bulman , Bruce A. Rosa, Xin Gao, Ryan Chugani, Mingzhou Zhou, Jon Helander, Paul J Brindley, Chih-Chung Tseng, Iain R Greig, Judy Sakanari, Scott A. Wildman, Raffi Aroian, James W. Janetka, Makedonka Mitreva

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Abstract

The enormous prevalence of infections caused by parasitic nematodes worldwide, coupled to the rapid emergence of their resistance to commonly used anthelmintic drugs, presents an urgent need for the discovery of new drugs. Herein, we have identified several classes of small molecules with broad spectrum activity against these pathogens. Previously, we reported the identification of carnitine palmitoyltransferases (CPTs) as a representative class of enzymes as potential targets for metabolic chokepoint intervention that was elucidated from a combination of chemogenomic screening and experimental testing in nematodes. Expanding on these previous findings, we have discovered that several chemical classes of known small molecule inhibitors of mammalian CPTs have potent activity as anthelmintics. Cross-clade efficacy against a broad spectrum of adult parasitic nematodes was demonstrated for multiple compounds from different series. Several analogs of these initial hit compounds were designed and synthesized. The compounds we report represent a good starting point for further lead identification and optimization for development of new anthelmintic drugs with broad spectrum activity and a novel mechanism of action.
Original languageEnglish
Pages (from-to)1130–1145
Number of pages16
JournalACS Infectious Diseases
Volume4
Issue number7
Early online date2 May 2018
DOIs
Publication statusPublished - 13 Jul 2018

Keywords

  • Parasitic nematodes
  • hookworm
  • whipworm
  • filarial nematode
  • whole worm assay
  • in vitro
  • in vivo
  • target class repurposing
  • carnitine palmitoyltransferase (CPT)
  • bioaccumulation
  • anthelmintic

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  • Cite this

    Tyagi, R., Maddirala, A. R., Elfawal, M., Fischer, C., Bulman , C. A., Rosa, B. A., Gao, X., Chugani, R., Zhou, M., Helander, J., Brindley, P. J., Tseng, C-C., Greig, I. R., Sakanari, J., Wildman, S. A., Aroian, R., Janetka, J. W., & Mitreva, M. (2018). Small Molecule Inhibitors of Metabolic Enzymes Repurposed as a New Class of Anthelmintics. ACS Infectious Diseases, 4(7), 1130–1145. https://doi.org/10.1021/acsinfecdis.8b00090