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Selective screening of antiparasitic substances
Wernerová, Klára ; Mach, Jan (advisor) ; Kovářová, Julie (referee)
The mitochondrion is the key organelle of the cell. It is involved in energy metabolism, the Krebs cycle, the respiratory chain, and the formation of Fe-S clusters, which form the structure of many proteins. Therefore, disruption of the mitochondria is usually fatal to the cell, especially if it contains only one mitochondrion, as is the case in Trypanosoma brucei brucei. The T. b. brucei parasite has become the primary model organism for our study because its basic biochemical processes are already well described, including mitochondrial metabolism, and it is also easy to cultivate in the laboratory. Other model organisms we used in this study were Leishmania mexicana, Cryptococcus neoformans and Candida albicans. All these organisms are causative agents of serious diseases, and although there are drugs against them, new drugs need to be developed due to the frequent emergence of resistances. Mitochondria-targeting drugs are promising for the pharmaceutical industry. In this work, we investigate the efficacy of compounds whose structure is composed of a mitochondrial phosphonium anchor linked to a carbon chain. These substances are capable of incorporation into the mitochondrial membranes. The work not only focuses on comparing the potency of the tested substances in selected model organisms, but...
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Iron homeostasis in malaria
Wernerová, Klára ; Šuťák, Róbert (advisor) ; Voleman, Luboš (referee)
Although malaria is a well-studied infectious disease, we are still unable to fight it effectively, as evidenced by a large number of infected people. Many drugs are available against malaria. However, because of incessantly emerging resistances, new, more effective antimalarials need to be developed. One possibility is to target the parasite's iron metabolism, the essential element of all organisms. Iron participates in DNA synthesis, respiration, energy production. It acts as a cofactor of ribonucleotide reductase, and metalloproteins with FeS clusters or heme. During the infection, the parasite must compete with the host for nutrients, including iron. The mechanism of iron uptake or excretion in malaria parasite is not completely clear. Only two iron transporters are known, but it is already evident, that there must be more of them. The Plasmodium parasite digests a large amount of hemoglobin, which is degraded into free heme and denatured globin. Free heme is toxic to the cell though. Plasmodium defends itself from the toxicity of free heme by forming chemically inert hemozoin. This unique mechanism of protection against the free heme toxicity is very useful for Plasmodium and other blood parasites, but it also becomes an advantageous target for drugs because the mechanism is present only in...
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