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Simon Oliver Weiland, Die Arbeit basiert auf einem gleichlautenden Artikel, Universität Innsbruck, Masterarbeit, 2021, (VLID)5658761

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

Research undertaken for this thesis aimed to detect and identify stellar variability in the database of the Japan/New Zealand MOA collaboration. The database of stars collected by the MOA project provided an extensive source of raw data for analysis. Detection of stellar variability was performed by several C++ programs created by the author, which incorporated the Welch and Stetson variability index, the Schwarzenburg-Czerny period folding program, a microlensing modelling program and a transit, detection program. The search for stellar variability produced 83 Cepheid variables, 265 long period variables, 59 eclipsing binaries and 6 potential microlensing events. Sixteen potentially interesting variations that could correspond to planetary transits were also detected. The folded lightcurve of one of the potential transits was categorised as a 'very interesting transit' and 15 were categorised as 'interesting transits'. The search for planetary transits ultimately proved unsuccessful, however, a detailed statistical study of the MOA data revealed several alterations concerning observational procedures which could be made to optimise the MOA data for any future search for planetary transits.

Research undertaken for this thesis aimed to detect and identify stellar variability in the database of the Japan/New Zealand MOA collaboration. The database of stars collected by the MOA project provided an extensive source of raw data for analysis. Detection of stellar variability was performed by several C++ programs created by the author, which incorporated the Welch and Stetson variability index, the Schwarzenburg-Czerny period folding program, a microlensing modelling program and a transit, detection program. The search for stellar variability produced 83 Cepheid variables, 265 long period variables, 59 eclipsing binaries and 6 potential microlensing events. Sixteen potentially interesting variations that could correspond to planetary transits were also detected. The folded lightcurve of one of the potential transits was categorised as a 'very interesting transit' and 15 were categorised as 'interesting transits'. The search for planetary transits ultimately proved unsuccessful, however, a detailed statistical study of the MOA data revealed several alterations concerning observational procedures which could be made to optimise the MOA data for any future search for planetary transits.

Research undertaken for this thesis aimed to detect and identify stellar variability in the database of the Japan/New Zealand MOA collaboration. The database of stars collected by the MOA project provided an extensive source of raw data for analysis. Detection of stellar variability was performed by several C++ programs created by the author, which incorporated the Welch and Stetson variability index, the Schwarzenburg-Czerny period folding program, a microlensing modelling program and a transit, detection program. The search for stellar variability produced 83 Cepheid variables, 265 long period variables, 59 eclipsing binaries and 6 potential microlensing events. Sixteen potentially interesting variations that could correspond to planetary transits were also detected. The folded lightcurve of one of the potential transits was categorised as a 'very interesting transit' and 15 were categorised as 'interesting transits'. The search for planetary transits ultimately proved unsuccessful, however, a detailed statistical study of the MOA data revealed several alterations concerning observational procedures which could be made to optimise the MOA data for any future search for planetary transits.

Research undertaken for this thesis aimed to detect and identify stellar variability in the database of the Japan/New Zealand MOA collaboration. The database of stars collected by the MOA project provided an extensive source of raw data for analysis. Detection of stellar variability was performed by several C++ programs created by the author, which incorporated the Welch and Stetson variability index, the Schwarzenburg-Czerny period folding program, a microlensing modelling program and a transit, detection program. The search for stellar variability produced 83 Cepheid variables, 265 long period variables, 59 eclipsing binaries and 6 potential microlensing events. Sixteen potentially interesting variations that could correspond to planetary transits were also detected. The folded lightcurve of one of the potential transits was categorised as a 'very interesting transit' and 15 were categorised as 'interesting transits'. The search for planetary transits ultimately proved unsuccessful, however, a detailed statistical study of the MOA data revealed several alterations concerning observational procedures which could be made to optimise the MOA data for any future search for planetary transits.

Research undertaken for this thesis aimed to detect and identify stellar variability in the database of the Japan/New Zealand MOA collaboration. The database of stars collected by the MOA project provided an extensive source of raw data for analysis. Detection of stellar variability was performed by several C++ programs created by the author, which incorporated the Welch and Stetson variability index, the Schwarzenburg-Czerny period folding program, a microlensing modelling program and a transit, detection program. The search for stellar variability produced 83 Cepheid variables, 265 long period variables, 59 eclipsing binaries and 6 potential microlensing events. Sixteen potentially interesting variations that could correspond to planetary transits were also detected. The folded lightcurve of one of the potential transits was categorised as a 'very interesting transit' and 15 were categorised as 'interesting transits'. The search for planetary transits ultimately proved unsuccessful, however, a detailed statistical study of the MOA data revealed several alterations concerning observational procedures which could be made to optimise the MOA data for any future search for planetary transits.

Christmas Card 1922 with image of woman holding a bucket.

Christmas Card 1922 designed by Albert Rutherston and printed by Oliver Simon.

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Laetirobin, isolated from a parasitic fungus host–plant relationship, was synthesized in six practical steps with an overall yield of 12% from commercially available 2,4-dihydroxyacetophenone. Because the product is a pseudosymmetric tetramer of benzo[b]furans, each step of the synthesis was designed to involve tandem operations. Highlights include: 1) the double Sonogashira reaction of a bis(alkyne), 2) the practical copper(I)-mediated formation of a bis(benzo[b]furan), and 3) the biomimetic [4+2] dimerization and unexpected cationic [5+2] annulation of gem-diaryl alkene precursors. Preliminary structure–activity relationship data between the isomeric [4+2] and [5+2] tetramers revealed only the natural product to possess promising anticancer potential. Specifically, laetirobin is capable of blocking tumor cell division (mitosis) and invoking programmed cell death (apoptosis).

Laetirobin (1) was isolated as a cytostatic lead from Laetiporus sulphureus growing parasitically on the black locust tree, Robinia pseudoacacia, by virtue of a reverse-immunoaffinity system. Using an LC/MS procedure, milligram quantities of laetirobin (1) were obtained, and the structure of 1 was elucidated by X-ray crystallography and confirmed by NMR spectroscopy. Preliminary cellular studies indicated that laetirobin (1) rapidly enters in tumor cells, blocks cell division at a late stage of mitosis, and invokes apoptosis.