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Kinases as drug targets

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. We have a long standing interest in kinases as targets for developing anthelminthics. Hence, we have identified PKs from nematodes, hosts, and DrugBank and classified them 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.


 Project information:

Citation:

Taylor CM, Martin J, Rao RU, Powell K, Abubucker S, Mitreva M. Using Existing Drugs as Leads for Broad Spectrum Anthelmintics Targeting Protein Kinases. Geary TG, ed. PLoS Pathogens. 2013;9(2):e1003149. doi:10.1371/journal.ppat.1003149.


Supplemental files:

Top orthologous groups from minimal kinome listed with the respective C. elegans protein, the kinase classification, E-value from the HMM, DrugBank target ID and compounds known to bind to the target, KO and IPR IDs, information regarding tissue expression in C. elegans, RNAi phenotype, and stage expression RNAseq data analyzed within a stage and across different stages:

Table:  TopOrthoGroups.xlsx

 
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