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Title: Chemo-enzymatic modification of cyclic peptides
Author: Dalponte, Luca
ISNI:       0000 0004 7432 0461
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2018
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The interest in cyclic peptides has grown exponentially in the last decade due to their promising therapeutic potential. Cyclization makes the molecules more compact and lowers the polarity by eliminating the charges on the N- and C- termini and improves the resistance to enzymatic degradation and in some cases the membrane permeability and bioavailability. Cyclic peptides proved to be able to modulate proteinprotein interactions, unlocking a medical area considered "undruggable" until recently. However, issues such as their challenging synthesis at large scale or modification and poor availability are often evident. A chemo-enzymatic approach involving posttranslational modifications such as prenylation, N-methylation, oxidation and others found in various natural peptides coupled with the recent advantages in the chemical synthesis of peptides has the potential to address this issue. Cyanobactins are a leading example as their biosynthetic machinery possess an extraordinary plasticity that allows the generation of molecules with the desired characteristics. We have identified two new biosynthetic gene clusters in Microcystis aeruginosa NIES-88 and Anabaena sp. UHCC-0232 and reported two novel prenyltransferases tailoring tryptophan. The enzymes exhibit a broad substrate tolerance processing cyclic and linear peptides as well as protected or unnatural Trp residues, but a different specificity towards derivatives of the natural prenyl donor DMAPP. Finally, we report the investigation of a hypothetical oxazoline dehydrogenase and its challenging expression as soluble protein. The identification of novel enzymes is essential for the design and generation of future drugs as it allows the incorporation of specific modifications that improve the properties of the molecules such as the PK/ADMET through prenylation or the bioactivity with the oxidation.
Supervisor: Jaspars, Marcel ; Houssen, Wael E. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Cyclic peptides ; Enzymes