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Investigating Pharmacological Targeting of G-Quadruplexes in the Human Malaria Parasite.

Abstract：

:The unique occurrence of G-quadruplexes in the AT-rich genome of human malaria parasite Plasmodium falciparum provides hints about their critical roles in parasite survival, pathogenesis, and host immune evasion. An intriguing question is whether these noncanonical structures can serve as molecular targets for small molecule-based interventions against malaria. In this study, we have investigated the pharmacological targeting of G-quadruplexes for parasite inhibition. We observed that bisquinolinium derivatives of 1,8-naphthyridine and pyridine affected the stability and molecular recognition properties of G-quadruplexes in telomeric and subtelomeric regions in P. falciparum. Parasite inhibition and cytotoxicity assays revealed that these ligands effectively inhibit parasite growth with minimal toxic effects in human cells. G-quadruplex interacting ligands caused degeneration and shortening of parasite telomeres. Ligand-induced perturbations in telomere homeostasis also affected transcriptional state of the subtelomeric region harboring antigenic variation genes. Taken together, our results suggest that quadruplex-ligand interaction disturbs telomeric/subtelomeric chromatin organization and induces DNA damage that consequently leads to parasite death. Our findings also draw attention to the striking differences in telomere dynamics in the protozoan parasite and human host that can be exploited for selective targeting of the telomeric quadruplex of the parasite as a potential antimalarial strategy.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Anas M,Sharma R,Dhamodharan V,Pradeepkumar PI,Manhas A,Srivastava K,Ahmed S,Kumar N

doi

10.1021/acs.biochem.7b00964

subject

Has Abstract

pub_date

2017-12-26 00:00:00

pages

6691-6699

issue

51

eissn

0006-2960

issn

1520-4995

journal_volume

56

pub_type

杂志文章

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