Wakai Theophilus N, Anzaku Dorathy O, Afolabi Israel S
Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Nigeria.
Covenant Applied Informatics and Communication Africa Centre of Excellence (CApIC-ACE), Covenant University, Ota, Ogun State, Nigeria.
Front Cell Infect Microbiol. 2025 Sep 10;15:1659175. doi: 10.3389/fcimb.2025.1659175. eCollection 2025.
This review examines the potential of disrupting telomere maintenance in as a novel antimalarial strategy. Telomeres are repetitive DNA-protein structures located at chromosome termini, where they preserve genome stability and protect against degradation. Telomere maintenance is crucial for rapid growth, genome integrity, and immune evasion in parasites. Unlike humans, maintains continuous telomerase activity and uses unique telomere-binding proteins across its lifecycle. These features drive parasite virulence and antigenic variation. Emerging evidence suggests that telomeres harbor G-quadruplex (G4) DNA structures, which help stabilize telomeres during replication and may be good targets for small molecules to disrupt their function. Additionally, the parasite depends heavily on its telomerase catalytic subunit, PfTERT, for survival. Inhibiting PfTERT has shown promising results in blocking telomere elongation and impairing replication. Targeting this parasite-specific telomere-telomerase axis may offer a strategic means to destabilize chromosomes, weaken immune evasion, and limit parasite survival, making it a promising antimalarial approach. However, researchers must consider the risks of off-target effects in future drug designs. Though current studies are limited and remain inconclusive, we suggest that future research should investigate combining telomere-directed therapies with existing antimalarials to help overcome resistance and improve treatment outcomes. Herein, we review advances in understanding telomere biology, highlighting its distinct structures, critical telomere-associated proteins, and roles in pathogenesis. We further explore how selective targeting could exploit an Achilles' heel in parasite survival, offering fresh possibilities for next-generation, parasite-specific malaria therapies.
本综述探讨了破坏疟原虫端粒维持作为一种新型抗疟策略的潜力。端粒是位于染色体末端的重复性DNA-蛋白质结构，在那里它们维持基因组稳定性并防止降解。端粒维持对于疟原虫的快速生长、基因组完整性和免疫逃避至关重要。与人类不同，疟原虫在其整个生命周期中保持持续的端粒酶活性并使用独特的端粒结合蛋白。这些特征驱动寄生虫的毒力和抗原变异。新出现的证据表明，疟原虫端粒含有G-四链体（G4）DNA结构，其在复制过程中有助于稳定端粒，并且可能是小分子破坏其功能的良好靶点。此外，疟原虫严重依赖其端粒酶催化亚基PfTERT来生存。抑制PfTERT在阻断端粒延长和损害复制方面已显示出有希望的结果。靶向这种寄生虫特异性的端粒-端粒酶轴可能提供一种使染色体不稳定、削弱免疫逃避和限制寄生虫生存的战略手段，使其成为一种有前景的抗疟方法。然而，研究人员在未来的药物设计中必须考虑脱靶效应的风险。尽管目前的研究有限且尚无定论，但我们建议未来的研究应调查将端粒导向疗法与现有抗疟药物联合使用，以帮助克服耐药性并改善治疗效果。在此，我们综述了在理解疟原虫端粒生物学方面的进展，强调了其独特的结构、关键的端粒相关蛋白以及在发病机制中的作用。我们进一步探讨了选择性靶向如何利用寄生虫生存中的致命弱点，为下一代寄生虫特异性疟疾治疗提供新的可能性。
