Investigating Pharmacological Targeting of G-Quadruplexes in the Human Malaria Parasite
Investigating Pharmacological Targeting of G-Quadruplexes in the Human Malaria Parasite
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DOI：
10.1021/acs.biochem.7b00964
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发表时间：
2017-12-26
期刊：
影响因子：
2.9
通讯作者：
Kumar, Niti
中科院分区：
文献类型：
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作者：
Anas, Mohammad;Sharma, Richa;Kumar, Niti
人类恶性疟原虫富含at的基因组中g -四联体的独特存在，为它们在寄生虫生存、发病和宿主免疫逃避中的关键作用提供了线索。一个有趣的问题是，这些非规范结构是否可以作为基于小分子的疟疾干预措施的分子靶标。在这项研究中，我们研究了g -四联体对寄生虫抑制的药理学靶点。我们观察到1,8-萘啶和吡啶的双喹啉衍生物影响了恶性疟原虫端粒和亚端粒区域g -四联体的稳定性和分子识别特性。寄生虫抑制和细胞毒性试验表明，这些配体有效地抑制寄生虫生长，对人体细胞的毒性作用最小。g -四重体相互作用配体引起寄生虫端粒退化和缩短。配体诱导的端粒稳态扰动也会影响含有抗原变异基因的亚端粒区域的转录状态。综上所述，我们的研究结果表明，四重配体相互作用扰乱了端粒/亚端粒染色质组织，诱导DNA损伤，从而导致寄生虫死亡。我们的研究结果还引起了人们对原生动物寄生虫和人类宿主端粒动力学的显著差异的关注，这些差异可以用于选择性靶向寄生虫端粒四重体作为潜在的抗疟疾策略。
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.