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

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.

SUBMITTER: Tyagi R

PROVIDER: S-EPMC6283408 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Tyagi Rahul R Maddirala Amarendar Reddy AR Elfawal Mostafa M Fischer Chelsea C Bulman Christina A CA Rosa Bruce A BA Gao Xin X Chugani Ryan R Zhou Mingzhou M Helander Jon J Brindley Paul J PJ Tseng Chih-Chung CC Greig Iain R IR Sakanari Judy J Wildman Scott A SA Aroian Raffi R Janetka James W JW Mitreva Makedonka M

ACS infectious diseases 20180514 7

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 chok ...[more]

PMID: 29718656

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

Publications

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

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