Proteins are involved in all vital processes in cells. As tools of the cell, they have regulatory or structure-giving functions. In protein and peptide engineering, attempts are made to understand how these biological systems function or to modify the physicochemical properties of peptides and proteins via non-natural amino acids with novel functional groups. In the present work, both aspects were investigated. The present work's first part deals with various fluorine modification applications in peptides and proteins. The element fluorine is very rarely found in natural biological systems. However, the unique properties of fluorine, such as the strongest electronegativity combined with extremely low polarizability, have led to its widespread application not only in pharmaceutical and agricultural chemistry. In protein and peptide engineering, fluorine modification often yields surprising results. In specifically tailored systems, the introduction of the element fluorine by applying fluorinated amino acids in the present doctoral thesis should be investigated both as a probe in different smaller peptide models using new methods (in situ surfaceenhanced infrared absorption spectroscopy (SEIRAS), 19F-MRI (magnetic resonance imaging) as well as AFM (atomic force microscopy) and on the other hand as an orthogonal tool to control protein folding kinetics. The peptidic systems investigated here include sequence lengths of up to 90 amino acids (AAs) in a linear arrangement or conjugate constructs consisting of a peptidic scaffold (26 AAs) decorated on the side chain with another peptide (up to 21 AAs). For each of these complex native systems, a chemical approach has been successfully established from an ensemble of the suitable resin, coupling conditions, use of specific building blocks, and selection of the TFA cleavage cocktail. Moreover, a universal method has been successfully elaborated to incorporate fluorinated amino acids into such complex systems reliably. In the second project, research was conducted to elucidate the regulatory function of G-protein coupled receptor 83 (GPR83). This receptor is expressed in brain regions responsible for energy metabolism, spatial learning, and stress regulation. At the beginning of the present work, the receptor was considered an "orphan" because its endogenous ligand was unknown. Studies indicated that the xi extracellular N-terminal domain (eNDo) influences the regulatory processes as an "inverse agonist". In the present work, this domain was mapped using a peptide library consisting of 13 members of varying lengths (10 to 56 AAs) with an overlapping design. Circular dichroism measurements were used to determine the secondary structure of the respective peptides. The meanwhile published endogenous ligand of GPR83, hPEN, was also synthesized in the present work, and a co-supplementation with the peptide library members was planned. However, through numerous biological assays, it was not possible to detect receptor activity by either hPEN or the synthetic portions of eNDo. Further research on the project was therefore terminated.
