Tullio Ilometsa tegevuse jälg Tartu Ülikoolis: The marks left by Tullio Ilomets' activities at the University of Tartu

Tullio Ilomets was a legendary person in the recent history of theUniversity of Tartu. He participated in the reconstruction of chemistry education and in establishing contemporary organic synthesis atthe post-war University. Initially Ilomets studied hydrocarbons withtriple bonds. Among many useful applications, these compounds werelater used as building blocks for the synthesis of plant protectionchemicals, known as pheromones. Later he became interested in theanalysis of complex mixtures of organic compounds of biological origin, including snake venoms, different types of medicinal mud samples, glycosides of plant extracts and complex mixtures of fermentation products, which can be considered precursors of contemporarydietary supplements.Ilomets was very deeply interested in the history of science, andhe established the excellent collection of scientific instruments exhibited at the University of Tartu Museum. Besides this academic interest in history, he actively participated in practical heritage conservation activities, for example, by studying the chemical compositionof building materials needed for the restoration of St. John’s Churchin Tartu.Ilomets had a great influence on students, increasing their professional skills, but more importantly, he had a strong impact on theirintellectual development. This kind of mentorship shaped the mindsof many generations of students and affected the entire communityof Estonian chemists

Bisubstrate Inhibitor Approach for Targeting Mitotic Kinase Haspin

During the past decade, the basophilic atypical kinase Haspin has emerged as a key player in mitosis responsible for phosphorylation of Thr3 residue of histone H3. Here, we report the construction of conjugates comprising an aromatic fragment targeted to the ATP-site of Haspin and a peptide mimicking the N-terminus of histone H3. The combination of effective solid phase synthesis procedures and a high throughput binding/displacement assay with fluorescence anisotropy readout afforded the development of inhibitors with remarkable subnanomolar affinity toward Haspin. The selectivity profiles of novel conjugates were established by affinity studies with a model basophilic kinase (catalytic subunit of cAMP-dependent protein kinase) and by a commercial 1-point inhibition assay with 43 protein kinases

Bifunctional Ligands for Inhibition of Tight-Binding Protein–Protein Interactions

The acknowledged potential of small-molecule therapeutics targeting disease-related protein–protein interactions (PPIs) has promoted active research in this field. The strategy of using small molecule inhibitors (SMIs) to fight strong (tight-binding) PPIs tends to fall short due to the flat and wide interfaces of PPIs. Here we propose a biligand approach for disruption of strong PPIs. The potential of this approach was realized for disruption of the tight-binding (<i>K</i>_D = 100 pM) tetrameric holoenzyme of cAMP-dependent protein kinase (PKA). Supported by X-ray analysis of cocrystals, bifunctional inhibitors (ARC-inhibitors) were constructed that simultaneously associated with both the ATP-pocket and the PPI interface area of the catalytic subunit of PKA (PKAc). Bifunctional inhibitor ARC-1411, possessing a <i>K</i>_D value of 3 pM toward PKAc, induced the dissociation of the PKA holoenzyme with a low-nanomolar IC₅₀, whereas the ATP-competitive inhibitor H89 bound to the PKA holoenzyme without disruption of the protein tetramer