Uusien tiatsolirakenteisten prolyylioligopeptidaasi-inhibiittorien synteesi

Prolyylioligopeptidaasi (PREP) on alfasynukleiinin tavoin yhdistetty useaan neurologiseen ja psykiatriseen sairauteen, joista tämän tutkimuksen kannalta kiinnostavin on parkinsonismi. Kyseinen entsyymi pilkkoo pienehköä peptideitä proliinipäästään. Sillä on myös havaittu olevan proteiini-proteiinivuorovaikutuksia esimerkiksi alfatubuliiniin, GAP-43:n ja alfasynukleiiniin. Myös PREP-inhibiittoreiden vaikutus alfasynukleiinin poistumiseen autofagian kautta on todennettu. Tiatsolirengas on heteroaromaattinen viisirengas, jossa on kaksi heteroatomia, rikki ja typpi. Kyseinen rengasrakenne löytyy lukuisista eri terapiaryhmästä. Tiatsolille esitettiin syneesireitti vuonna 1887, minkä jälkeen kyseiseen rakenteeseen liittyvää kirjallisuutta on julkaistu runsaasti ja sille tyypilliset kemialliset reaktiot tunnetaan suhteellisen hyvin. Tutkimuksen tarkoitus on laajentaa tutkimusryhmässä tehtyä pienimolekyylisiä PREP-inhibiittoreita koskevaa tutkimusta niiden tiatsolianalogeihin ja kehittää synteesireitti, jonka avulla voidaan tuottaa mahdollisimman monta erilaista molekyyliä. Tavoitteena on myös kerätä tietoa tuotettujen molekyylien vaikutuksesta prolyylioligopeptidaasiin tarkkailemalla niiden IC50-arvoja in vitro sekä vaikutusta alfasynukleiinin dimerisoitumiseen sekä poistumiseen autofagian kautta soluviljelmissä. Tietyissä rajoissa myös synteesireitin optimointi ja vaihtoehtoisten reaktioiden etsiminen on tutkimuksen tavoitteiden joukossa. Tutkimuksen edetessä synteesireitin saantoa saatiin osin parannettua ja osa tuotetuista uusista molekyyleistä osoitti biologista aktiivisuutta.Prolyloligopeptidase (PREP) and alphasynuclein are linked to various neurological and psychiatric conditions of which the most relevant considering this study is parkinsonism. PREP cleaves small peptides after a proline residue. It has also protein-protein ineractions with alphatubulin, GAP-43 and alphasynuclein. PREP inhibitors have been shown to have an effect to elimination of alphasyuclein via autophagy. Thiazole is a heteroaromatic compound with two heteroatoms (sulphur and nitrogen). Thiazole can be found as a structural component among various active pharmaceutical ingredients with wide array of indications. Synthetic route for thiazole was published in 1887 and a considerable amount of literature regarding the use of thiazole in medicinal and synthetic chemistry has been published. The aim of the study was to extend the the scope of research done in the research group on small-molecular thiazole-based PREP inhibitors. The goal was to develop a synthetic route to access a series of molecules and gain information of the possible biological activities of the produced compounds by determining their IC50-values in vitro, effect on dimerization of alphasynuclein and removal of alphasynuclein via autophagy in a cell culture. Optimization of the synthetic route and search of alternative reactions were among the aims to some extent. During the course of study yields of some steps of the synthesis were improved and some new molecules had biological activity

Critical infrastructure protection: emploeyer expectations for cyber security education in Finland

In the human factor of cyber security, high level technical experts are considered as multidisciplinary technical gurus who are familiar with every aspect of IT environments including operating systems, code languages and protocols. University curricula and guiding frameworks, such e.g. NICE Cyber Security Workforce Framework, are designed to produce professionals to match the endless needs of working life. The cornerstones of achieving good working results can be considered as the level of expertise competence of the employee performing the task, as well as combining personal skills and abilities with the competence profile of the given task. Does the cyber domain need slightly lower educated, vocational level employees? As part of the National Security Policy in Finland, the vocational qualification in information and communications technology has recently started to produce suitable workforce for cyber labor on the European Qualifications Framework level 4 (EQF-4). In this research paper we answer the question how well the vocational education meets the demands of the employers as suitable workforce in cyber security in Finland. The study also investigated what kind of cyber security employees the Finnish employers currently need; what is the required level of education, level of experience and direction of competence. The research data was collected through a structured questionnaire survey, which was directed to critical national infrastructure protection companies such as Finnish telecom operators, ICT service providers, defense sector, and other governmental actors. The questionnaire results were examined with quantitative methods. Based on our results, regarding the content of education at EQF4-level, employers believe that the emphasis should be placed on basic technical skills and adherence to guidelines, while choosing more detailed specific areas of expertise is less important at this level of education. Based on the responses, in general cyber security related work has higher education level requirements than EQF4-level could provide. The results of the study can be used as guidelines for the development of the future curricula and in the strategic leadership of companies employing cyber security professionals

5-aminothiazoles reveal a new ligand-binding site on prolyl oligopeptidase which is important for modulation of its protein-protein interaction-derived functions

Abstract: A series of novel 5-aminothiazole-based ligands for prolyl oligopeptidase (PREP) comprise selective, potent modulators of the protein-protein interaction (PPI)-mediated functions of PREP, although they are only weak inhibitors of the proteolytic activity of PREP. The disconnected structure-activity relationships are significantly more pronounced for the 5-aminothiazole-based ligands than for the earlier published 5-aminooxazole-based ligands. Furthermore, the stability of the 5-aminothiazole scaffold allowed exploration of wider substitution patterns than that was possible with the 5-aminooxazole scaffold. The intriguing structure-activity relationships for the modulation of the proteolytic activity and PPI-derived functions of PREP were elaborated by presenting a new binding site for PPI modulating PREP ligands, which was initially discovered using molecular modeling and later confirmed through point mutation studies. Our results suggest that this new binding site on PREP is clearly more important than the active site of PREP for the modulation of its PPI-mediated functions