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      Characterization of parasite-specific indels and their proposed relevance for selective anthelminthic drug targeting

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          Abstract

          Insertions and deletions (indels) are important sequence variants that are considered as phylogenetic markers that reflect evolutionary adaptations in different species. In an effort to systematically study indels specific to the phylum Nematoda and their structural impact on the proteins bearing them, we examined over 340,000 polypeptides from 21 nematode species spanning the phylum, compared them to non-nematodes and identified indels unique to nematode proteins in more than 3,000 protein families. Examination of the amino acid composition revealed uneven usage of amino acids for insertions and deletions. The amino acid composition and cost, along with the secondary structure constitution of the indels, were analyzed in the context of their biological pathway associations. Species-specific indels could enable indel-based targeting for drug design in pathogens/parasites. Therefore, we screened the spatial locations of the indels in the parasite’s protein 3D structures, determined the location of the indel and identified potential unique drug targeting sites. These indels could be confirmed by RNA-Seq data. Examples are presented that illustrate the close proximity of the indel to established small-molecule binding pockets that can potentially facilitate selective targeting to the parasites and bypassing their host, thus reducing or eliminating the toxicity of the potential drugs. The study presents an approach for understanding the adaptation of pathogens/parasites at a molecular level, and outlines a strategy to identify such nematode-selective targets that remain essential to the organism. With further experimental characterization and validation, it opens a possible channel for the development of novel treatments with high target specificity, addressing both host toxicity and resistance concerns.

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          Author and article information

          Journal
          101084138
          22395
          Infect Genet Evol
          Infect. Genet. Evol.
          Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases
          1567-1348
          1567-7257
          11 February 2016
          30 January 2016
          April 2016
          01 April 2017
          : 39
          : 201-211
          Affiliations
          [1 ]McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA
          [2 ]Carbone Cancer Center, School of Medicine and Public Health,University of Wisconsin, Madison, Wisconsin, USA
          [3 ]Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO, USA
          [4 ]Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
          [5 ]Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
          Author notes
          [* ]Author for Correspondence: Makedonka Mitreva, Tel: 1-314-286-2005, Fax: 1-314-286-1800, mmitreva@ 123456genome.wustl.edu
          [#]

          Equal contribution

          Article
          PMC4789095 PMC4789095 4789095 nihpa758388
          10.1016/j.meegid.2016.01.025
          4789095
          26829384
          29a06267-df34-46a6-9753-b8ed0829eb3e
          History
          Categories
          Article

          insertions and deletions,adaptation,spatial structures of proteins,drug targets,selective targeting,parasites,nematodes

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