Our group is interested in using peptides for the quantitative biophysical and structural analysis of protein-protein interactions in health and disease. Based on this, we develop lead peptides that modulate PPI for therapeutic purposes. To improve the lead peptides, we are developing new synthetic methods for peptide modifications. In my talk I will present a new approach for peptide cyclization during solid phase synthesis under highly acidic conditions1. Our approach involves simultaneous in situ deprotection, cyclization and TFA cleavage of the peptide, which is achieved by forming an amide bond between a lysine side chain and a succinic acid linker at the peptide N-terminus. The reaction proceeds via a highly active succinimide intermediate, which was isolated and characterized. Our new methodology is applicable for the formation of macrocycles in solid phase synthesis of peptides and organic molecules. We also developed a new general N-acetylation method for solid phase synthesis2,3. Malonic acid is used as precursor and the reaction proceeds by in situ formation of a reactive ketene intermediate at room temperature. Mechanism and implications of the method will be discussed.