Using existing drugs as leads for broad spectrum anthelmintics targeting protein kinases

• Published in: PLoS pathogens Vol. 9; no. 2; p. e1003149
• Main Authors: Taylor, Christina M, Martin, John, Rao, Ramakrishna U, Powell, Kerrie, Abubucker, Sahar, Mitreva, Makedonka
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2013; Public Library of Science (PLoS)
• Subjects: Agriculture; Animals; Anthelmintics; Anthelmintics - pharmacology; Biology; Brugia malayi - drug effects; Brugia malayi - genetics; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - genetics; Dosage and administration; Drug resistance in microorganisms; Genetics; Genomics; Haemonchus - drug effects; Haemonchus - genetics; Health aspects; Molecular Structure; Nematodes; Pharmacokinetics; Physiological aspects; Protein kinases; Protein Kinases - chemistry; Protein Kinases - genetics; Proteins; RNA Interference; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003149

As one of the largest protein families, protein kinases (PKs) regulate nearly all processes within the cell and are considered important drug targets. Much research has been conducted on inhibitors for PKs, leading to a wealth of compounds that target PKs that have potential to be lead anthelmintic drugs. Identifying compounds that have already been developed to treat neglected tropical diseases is an attractive way to obtain lead compounds inexpensively that can be developed into much needed drugs, especially for use in developing countries. In this study, PKs from nematodes, hosts, and DrugBank were identified and classified into kinase families and subfamilies. Nematode proteins were placed into orthologous groups that span the phylum Nematoda. A minimal kinome for the phylum Nematoda was identified, and properties of the minimal kinome were explored. Orthologous groups from the minimal kinome were prioritized for experimental testing based on RNAi phenotype of the Caenorhabditis elegans ortholog, transcript expression over the life-cycle and anatomic expression patterns. Compounds linked to targets in DrugBank belonging to the same kinase families and subfamilies in the minimal nematode kinome were extracted. Thirty-five compounds were tested in the non-parasitic C. elegans and active compounds progressed to testing against nematode species with different modes of parasitism, the blood-feeding Haemonchus contortus and the filarial Brugia malayi. Eighteen compounds showed efficacy in C. elegans, and six compounds also showed efficacy in at least one of the parasitic species. Hypotheses regarding the pathway the compounds may target and their molecular mechanism for activity are discussed.