The pathogenic fungus Aspergillus fumigatus utilizes a cyclic ferrioxamine E (FOXE) siderophore to acquire iron from the host. Biomimetic FOXE analogues were labeled with gallium-68 for molecular imaging with PET. [68Ga]Ga(III)-FOXE analogues were internalized in A. fumigatus cells via Sit1. Uptake of [68Ga]Ga(III)-FOX 2-5, the most structurally alike analogue to FOXE, was high by both A. fumigatus and bacterial Staphylococcus aureus. However, altering the ring size provoked species-specific uptake between these two microbes: ring size shortening by one methylene unit (FOX 2-4) increased uptake by A. fumigatus compared to that by S. aureus, whereas lengthening the ring (FOX 2-6 and 3-5) had the opposite effect. These results were consistent both in vitro and in vivo, including PET imaging in infection models. Overall, this study provided valuable structural insights into the specificity of siderophore uptake and, for the first time, opened up ways for selective targeting and imaging of microbial pathogens by siderophore derivatization.

• MeSH
• Aspergillus fumigatus * metabolismus   chemie   MeSH
• aspergilóza * diagnostické zobrazování   mikrobiologie   MeSH
• biomimetické materiály chemie   metabolismus   MeSH
• cyklické peptidy MeSH
• deferoxamin chemie   MeSH
• druhová specificita MeSH
• myši MeSH
• pozitronová emisní tomografie * metody   MeSH
• radioizotopy galia * chemie   MeSH
• siderofory * chemie   metabolismus   MeSH
• Staphylococcus aureus * metabolismus   MeSH
• železité sloučeniny chemie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cyklické peptidy MeSH
• deferoxamin MeSH
• ferrioxamine E MeSH Prohlížeč
• Gallium-68 MeSH Prohlížeč
• radioizotopy galia * MeSH
• siderofory * MeSH
• železité sloučeniny MeSH

Iron, as an essential micronutrient, plays a crucial role in host-pathogen interactions. In order to limit the growth of the pathogen, a common strategy of innate immunity includes withdrawing available iron to interfere with the cellular processes of the microorganism. Against that, unicellular parasites have developed powerful strategies to scavenge iron, despite the effort of the host. Iron-sequestering compounds, such as the approved and potent chelator deferoxamine (DFO), are considered a viable option for therapeutic intervention. Since iron is heavily utilized in the mitochondrion, targeting iron chelators in this organelle could constitute an effective therapeutic strategy. This work presents mitochondrially targeted DFO, mitoDFO, as a candidate against a range of unicellular parasites with promising in vitro efficiency. Intracellular Leishmania infection can be cleared by this compound, and experimentation with Trypanosoma brucei 427 elucidates its possible mode of action. The compound not only affects iron homeostasis but also alters the physiochemical properties of the inner mitochondrial membrane, resulting in a loss of function. Furthermore, investigating the virulence factors of pathogenic yeasts confirms that mitoDFO is a viable candidate for therapeutic intervention against a wide spectrum of microbe-associated diseases.

• Klíčová slova
• chelation, iron, mitochondria, parasites, protists,
• MeSH
• antiinfekční látky * MeSH
• antiparazitární látky farmakologie   MeSH
• chelátory železa farmakologie   terapeutické užití   MeSH
• deferoxamin chemie   MeSH
• mitochondrie MeSH
• železo * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antiinfekční látky * MeSH
• antiparazitární látky MeSH
• chelátory železa MeSH
• deferoxamin MeSH
• železo * MeSH

Angiogenesis has a pivotal role in tumor growth and the metastatic process. Molecular imaging was shown to be useful for imaging of tumor-induced angiogenesis. A great variety of radiolabeled peptides have been developed to target αvβ3 integrin, a target structure involved in the tumor-induced angiogenic process. The presented study aimed to synthesize deferoxamine (DFO)-based c(RGD) peptide conjugate for radiolabeling with gallium-68 and perform its basic preclinical characterization including testing of its tumor-imaging potential. DFO-c(RGDyK) was labeled with gallium-68 with high radiochemical purity. In vitro characterization including stability, partition coefficient, protein binding determination, tumor cell uptake assays, and ex vivo biodistribution as well as PET/CT imaging was performed. [68Ga]Ga-DFO-c(RGDyK) showed hydrophilic properties, high stability in PBS and human serum, and specific uptake in U-87 MG and M21 tumor cell lines in vitro and in vivo. We have shown here that [68Ga]Ga-DFO-c(RGDyK) can be used for αvβ3 integrin targeting, allowing imaging of tumor-induced angiogenesis by positron emission tomography.

• Klíčová slova
• PET imaging, RGD peptides, deferoxamine, integrins, radiodiagnostics,
• MeSH
• deferoxamin analogy a deriváty   chemická syntéza   chemie   MeSH
• glioblastom diagnostické zobrazování   MeSH
• integrin alfaVbeta3 metabolismus   MeSH
• lidé MeSH
• myši inbrední BALB C MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• patologická angiogeneze diagnostické zobrazování   MeSH
• počítačová rentgenová tomografie metody   MeSH
• pozitronová emisní tomografie metody   MeSH
• radioizotopy galia chemie   MeSH
• tkáňová distribuce MeSH
• transplantace heterologní MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• deferoxamin MeSH
• Gallium-68 MeSH Prohlížeč
• integrin alfaVbeta3 MeSH
• radioizotopy galia MeSH

Flavonoids have been demonstrated to possess miscellaneous health benefits which are, at least partly, associated with iron chelation. In this in vitro study, 26 flavonoids from different subclasses were analyzed for their iron chelating activity and stability of the formed complexes in four patho/physiologically relevant pH conditions (4.5, 5.5, 6.8, and 7.5) and compared with clinically used iron chelator deferoxamine. The study demonstrated that the most effective iron binding site of flavonoids represents 6,7-dihydroxy structure. This site is incorporated in baicalein structure which formed, similarly to deferoxamine, the complexes with iron in the stoichiometry 1:1 and was not inferior in all tested pH to deferoxamine. The 3-hydroxy-4-keto conformation together with 2,3-double bond and the catecholic B ring were associated with a substantial iron chelation although the latter did not play an essential role at more acidic conditions. In agreement, quercetin and myricetin possessing all three structural requirements were similarly active to baicalein or deferoxamine at the neutral conditions, but were clearly less active in lower pH. The 5-hydroxy-4-keto site was less efficient and the complexes of iron in this site were not stable at the acidic conditions. Isolated keto, hydroxyl, methoxyl groups or an ortho methoxy-hydroxy groups were not associated with iron chelation at all.

• MeSH
• chelátory železa chemie   MeSH
• deferoxamin chemie   MeSH
• flavanony chemie   MeSH
• flavonoidy chemie   MeSH
• flavony chemie   MeSH
• isoflavony chemie   MeSH
• koncentrace vodíkových iontů MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-hydroxyflavanone MeSH Prohlížeč
• chelátory železa MeSH
• daidzein MeSH Prohlížeč
• deferoxamin MeSH
• flavanony MeSH
• flavone MeSH Prohlížeč
• flavonoidy MeSH
• flavony MeSH
• isoflavony MeSH

High resolution separation of metalloproteins and other iron compounds based on native gel electrophoresis followed by 59Fe autoradiography is described. Lysates of mouse spleen erythroid cells metabolically labeled with 59Fe-transferrin were separated on 3-20% polyacrylamide gradient gels in the presence of Triton X100 and detected by autoradiography. In addition to ferritin and hemoglobin, several compounds characterized by their binding of iron under different conditions were described. Iron chelatable by desferrioxamine migrated in the region where several high-molecular weight compounds were detected by silver staining. The technique is nondissociative, allowing identification of iron compounds with the use of specific antibodies. Cellular iron transport and the action of iron chelators on specific cellular targets can be investigated in many small biological samples in parallel.

• MeSH
• autoradiografie MeSH
• chelátory železa chemie   MeSH
• deferoxamin chemie   MeSH
• elektroforéza v polyakrylamidovém gelu MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• senzitivita a specificita MeSH
• ultrafiltrace MeSH
• železo chemie   izolace a purifikace   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory železa MeSH
• deferoxamin MeSH
• železo MeSH