Site Covalent Modification of Methionyl Peptides for the Production of FRET Complexes

• Published in: Chemistry : a European journal Vol. 21; no. 47; pp. 17023 - 17034
• Main Authors: Jadhav, Pramodkumar D., Shen, Jianheng, Sammynaiken, Ramaswami, Reaney, Martin J. T.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 16.11.2015; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: Alkylation; Amino Acids - chemistry; Biological Phenomena; Chemistry; Chemistry, Multidisciplinary; Coumarin; Coumarins - chemistry; Derivatives; Europium - chemistry; FRET; Fretting; lanthanides; Lanthanoid Series Elements - chemistry; Magnetic Resonance Spectroscopy; Methionine; Methionine - analogs & derivatives; Methionine - chemistry; natural products; Nuclei; Peptides; Peptides - chemistry; Peptides, Cyclic - chemistry; Photons; Physical Sciences; Science & Technology; Solvents; SULFOXIDE; peptides; CYCLIC-PEPTIDES; BINDING-PROTEINS; lanthanides; PROBES; natural products; CYCLOLINOPEPTIDES; TERBIUM(III); LUMINESCENCE; REDUCTION; methionine; EUROPIUM(III); alkylation; FRET; SEPARATION
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201502699

Flax cyclic peptides (orbitides, linusorbs (LOs)) [1–8‐NαC],[1‐MetO2]‐linusorb B1 ([MetO2]‐LO1) and [1–9‐NαC],[1‐MetO2]‐linusorb B2 ([MetO2]‐LO2) are biologically active. These LOs lack active nuclei commonly used in peptide modification. We have developed reactions to activate methionine methyl sulphide to produce stable derivatives. In these reactions, LOs are converted to sulfonium intermediates and subsequently to derivatives containing active nuclei while preserving their fundamental structures. The reaction conditions preserved cyclic peptide fundamental structure and organic solvent solubility. [Met]‐LO1 and [Met]‐LO2 analogues containing activated groups (CN, COOEt, and NH2) in the form of methionine, methionine (S)‐oxide, and methionine (S,S)‐dioxide amino acids were synthesized and characterized by LCMS and 1D and 2D NMR spectroscopy. Coumarin orbitide complexes produced in this manner bind Eu3+ yielding FRET compounds that absorb energy through coumarin antennae and emit photons at lanthanide wavelengths. Bioconjugation toolbox: Click‐based site‐selective modification of cyclic peptides through methionine has been found to afford stable analogues (see figure). The method has a broad substrate scope, whereby peptide‐based hybrid materials with useful optical and therapeutic functions might be synthesized. The utility of the protocol is marked for peptides that contain few functional groups and are compatible with organic solvents.