4.2 Article

Morpholino antisense oligo inhibits trans-splicing of pre-inositol 1,4,5-trisphosphate receptor mRNA of Trypanosoma cruzi and suppresses parasite growth and infectivity

Journal

PARASITOLOGY INTERNATIONAL
Volume 65, Issue 3, Pages 175-179

Publisher

ELSEVIER IRELAND LTD
DOI: 10.1016/j.parint.2015.12.001

Keywords

Trypanosoma cruzi; Morpholino antisense oligo; Inositol 1,4,5-trisphosphate receptor; Trans-splicing

Categories

Funding

  1. JSPS KAKENHI [15 K08452, 24390102]
  2. Pharmacological Research Foundation, Tokyo
  3. Foundation of Strategic Research Projects in Private Universities from the Ministry of Education, Culture, Sport, Science, and Technology, Japan [S1201013]
  4. Grants-in-Aid for Scientific Research [16K15268, 24390102, 25670205] Funding Source: KAKEN

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Morpholino antisense oligos (MAOs) are used to investigate physiological gene function by inhibiting gene translation or construction of specific alternative splicing variants by blocking cis-splicing. MAOs are attractive drug candidates for viral- and bacterial-infectious disease therapy because of properties such as in vivo stability and specificity to target genes. Recently, we showed that phosphorothioate antisense oligos against Trypanosoma cruzi inositol 1,4,5-trisphosphate receptor (TcIP3R) mRNA inhibit the parasite host cell infection. In the present study, we identified the spliced leader (SL) acceptor of pre-TcIP3R mRNA and synthesized MAO, which inhibited trans-splicing of the transcript (MAO-1). MAO-1 was found to inhibit the addition of SL-RNA to pre-TcIP3R mRNA by real-time RT-PCR analysis. Treatment of the parasites with MAO-1 significantly impaired the growth and infectivity into host cells. These results indicate that MAO-1 is a potential novel drug for Chagas disease and that MAOs inhibiting trans-splicing can be used to investigate the physiology of trypanosomal genes leading to the development of novel drugs. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

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