AbstractsBiology & Animal Science

The human tissue kallikreins (KLKs) form a family of 15 closely related serine proteases (KLK1-15). KLK3 is better known as prostate specific antigen (PSA) and it is highly prostate-specific. Kallikreins are attracting increased attention due to their role as biomarkers for screening, diagnosis, and monitoring of various cancers. Although PSA is a very useful marker for prostate cancer in the blood, the expression level of PSA is higher in normal prostatic epithelium than in tumour tissue, and it is further reduced in poorly differentiated tumours. It has been postulated that PSA activators (stimulating compounds) could be beneficial for patients with prostate cancer. The development of peptides as clinically useful drugs is greatly limited by their poor in vivo stability and low bioavailability. As the problems in using peptides as drugs are mainly arising from the peptide backbone, the focus for synthesizing peptide mimicking compounds is on the peptide backbone and how to replace it. The aim of this work was to replace the central disulfide bridge in the most potent PSA activating peptide C-4 by a hydrocarbon linker that had been previously synthesized in the research group. Two strategies for synthesis of the pseudopeptides were applied: a) synthesis of all peptide bonds on solid support by tailoring the reactions for this particular peptide, and b) synthesis of a monocyclic pseudopeptide in solution that could be incorporated directly into the standard protocol of solid phase peptide synthesis. The first strategy (a) proved to be tedious and would have required a lot of optimization to be successful. The cleavage conditions of the orthogonal protecting groups were not directly compatible with synthesis on solid support. The second strategy (b) also proved to be tedious, epimerization at the histidine residue was very prone in the solution phase even with standard peptide coupling reagents. However, the possibility to monitor all steps of the synthesis and to purify intermediate products made this synthetic route more attractive for this type of pseudopetide. The work in this master thesis resulted in a useful strategy to synthesise the desired pseudopeptides. Vävnadskallikreinerna (KLK) bildar en familj av 15 närbesläktade serinproteaser (KLK1-15). KLK3 är bättre känd som prostata specifikt antigen (PSA). Ett ökat intresse gentemot kallikreinerna har visats pga. deras användning som biomarkers i screening, diagnosering och uppföljning av olika former av cancer. Även om PSA är en mycket användbar marker för prostata cancer i blod, är halten av PSA högre i normal prostatisk vävnad än i tumörvävnad. Det har föreslagits att föreningar som stimulerar PSA kunde vara gynnsamma for patienter med prostata cancer. Utvecklingen av peptider som kliniskt användbara läkemedel är synnerligen begränsad av deras föga in vivo stabilitet och låga biotillgänglighet. Eftersom själva stommen av peptiden orsakar de största problemen är stommen och hur den kunde ersättas i fokus för syntetisering av föreningar som mimikerar…