Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC₅₀ values down to 49 nM. The compounds also block parasite proliferation (e.g., VUF13525 (20b): T. brucei rhodesiense IC₅₀ = 60 nM, T. brucei brucei IC₅₀ = 520 nM, T. cruzi = 7.6 μM), inducing a typical multiple nuclei and kinetoplast phenotype without being generally cytotoxic. The mode of action of 20b was investigated with recombinantly engineered trypanosomes expressing a cAMP-sensitive FRET sensor, confirming a dose-response related increase of intracellular cAMP levels in trypanosomes. Our findings further validate the TbrPDEB family as antitrypanosomal target.

SUMMARYForaging ants and bees use path-integration vectors and landmark cues for navigation. When in particular experimental paradigms the two types of information -vector-based and landmark-based information -are made to compete with each other, the insect may weight either source more heavily depending on the navigational context and the animalʼs motivational state. Here we studied the effects of a displaced nest mark on the homing performances of Cataglyphis ants. Foragers were trained to shuttle between the nest, which was marked by a black cylinder (the beacon), and an artificial feeder. Trained ants were captured at the feeder and transferred to a distant test field, where they experienced the nest mark at various positions relative to their home vector. When the beacon was positioned to one side of the point of release, the ants slightly drifted towards the beacon right at the start of their inbound run, but thereafter resumed their home-vector courses. When the nest mark appeared to one side further down the homing course, the ants set off in the home-vector direction, but then gradually drifted towards the beacon. The distance, at which this occurred, and the antsʼ drift from the home-vector course were very similar across test conditions. During the final search for the nest, landmark information dominated the antsʼ path integrator. The results clearly show that nest-mark memories are effective during the entire vector-based homeward course, but that they are either only partly activated or partly used unless the state of the antsʼ path integrator is close to zero.

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