DNA topoisomerases in apicomplexan parasites: promising targets for drug discovery

Abstract

The phylum Apicomplexa includes a large group of protozoan parasites responsible for a wide range of animal and human diseases. Destructive pathogens, such as Plasmodium falciparum and Plasmodium vivax, causative agents of human malaria, Cryptosporidium parvum, responsible of childhood diarrhoea, and Toxoplasma gondii, responsible for miscarriages and abortions in humans, are frequently associated with HIV immunosuppression in AIDS patients. The lack of effective vaccines, along with years of increasing pressure to eradicate outbreaks with the use of drugs, has favoured the formation of multidrug resistant strains in endemic areas. Almost all apicomplexan of medical interest contain two endosymbiotic organelles that contain their own mitochondrial and apicoplast DNA. Apicoplast is an attractive target for drug testing because in addition to harbouring singular metabolic pathways absent in the host, it also has its own transcription and translation machinery of bacterial origin. Accordingly, apicomplexan protozoa contain an interesting mixture of enzymes to unwind DNA from eukaryotic and prokaryotic origins. On the one hand, the main mechanism of DNA unwinding includes the scission of one-type I-or both DNA strands-type II eukaryotic topoisomerases, establishing transient covalent bonds with the scissile end. These enzymes are targeted by camptothecin and etoposide, respectively, two natural drugs whose semisynthetic derivatives are currently used in cancer chemotherapy. On the other hand, DNA gyrase is a bacterial-borne type II DNA topoisomerase that operates within the apicoplast and is effectively targeted by bacterial antibiotics like fluoroquinolones and aminocoumarins. The present review is an update on the new findings concerning topoisomerases in apicomplexan parasites and the role of these enzymes as targets for therapeutic agents.

Droplet Microfluidics Platform for Highly Sensitive and Quantitative Detection of Malaria-Causing Plasmodium Parasites Based on Enzyme Activity Measurement

“…1 Even in its present form, REEAD-on-a-Chip requires no specialized skills, and may be of direct use at community hospitals in non-endemic regions where lack of experience among technicians currently results in misdiagnoses and reporting delays. 2 Also, since the candidate enzyme, pTopI, is a potential new drug target in the combat against multi-drug resistant malaria 25, 26 , the presented REEAD-on-a-Chip would be an attractive setup for high-throughput drug screening. Finally, with the potential future development of REEAD substrates specific to other relevant enzyme activities the presented REEAD-on-a-Chip setup may form the basis for a more generic platform for nano-medicine or other purposes within applied or basic science.…”

Replacement of the Human Topoisomerase Linker Domain with the Plasmodial Counterpart Renders the Enzyme Camptothecin Resistant

“…This finding may open the way in exploiting the structural-dynamical properties of linkers from topoisomerase IB from different species to test their role in drug reactivity with the final aim to develop drugs selectively targeting topoisomerase IB from different species [31]. With this aim in mind we have characterized the linker domain of Top1 from the malaria causing pathogenic organism, Plasmodium falciparum .…”

Towards an immunosense vaccine to prevent toxoplasmosis: Protective Toxoplasma gondii epitopes restricted by HLA-A*0201

“…This work suggests that T. gondii infection might contribute to certain motor, cognitive, and behavioral abnormalities[6]. Currently, additional medicines for the active infection without associated hypersensitivity and toxicity, curative medicines for the currently untreatable latent bradyzoite form of the parasite, and a vaccine to prevent infection with this parasite are being sought[7–11]. There have been previous studies, which indicated that peptide formulations are effective at inducing immune responses to this and other infectious agents in murine and human hosts[12–16].…”