Solid-Phase Synthesis of Caged Luminescent Peptides via Side Chain Anchoring.
Daan SondagJurriaan J A HemingDennis W P M LöwikElena A KrivosheyevaDenise LejeuneMark van GeffenCornelis Van't VeerWaander L van HeerdeMarjolijn C J BeensBrian H M KuijpersThomas J BoltjeFloris P J T RutjesPublished in: Bioconjugate chemistry (2023)
The synthesis of caged luminescent peptide substrates remains challenging, especially when libraries of the substrates are required. Most currently available synthetic methods rely on a solution-phase approach, which is less suited for parallel synthesis purposes. We herein present a solid-phase peptide synthesis (SPPS) method for the synthesis of caged aminoluciferin peptides via side chain anchoring of the P 1 residue. After the synthesis of a preliminary test library consisting of 40 compounds, the synthetic method was validated and optimized for up to >100 g of resin. Subsequently, two separate larger peptide libraries were synthesized either having a P 1 = lysine or arginine residue containing in total 719 novel peptide substrates. The use of a more stable caged nitrile precursor instead of caged aminoluciferin rendered our parallel synthetic approach completely suitable for SPPS and serine protease profiling was demonstrated using late-stage aminoluciferin generation.