The development of organometallic OBOC peptide libraries and sequencing of N-terminal rhenium(I) tricarbonyl-containing peptides utilizing MALDI tandem mass spectrometry

Abstract

The development of peptide-based imaging agents through screening of large peptide libraries is hindered by the additional requirement of a radionuclide−chelator complex that can negatively affect the binding properties of the peptide. Herein, we report N-terminal rhenium(I)tricarbonyl OBOC (one-bead, one-compound) peptide libraries for use in the direct screening of potential imaging agents. The rhenium(I) tricarbonyl is incorporated directly in the library as an imaging entity surrogate to account for the presence of a technetium-99m radionuclide chelate. The identification of unknown organometallic peptides on single beads is successfully accomplished through MALDI tandem mass spectrometry, preceded by a systematic investigation of the effects of a variety of N-terminal rhenium(I) tricarbonyl chelates on peptide fragmentation patterns.Résumé : Le développement d'agents d'imagerie peptidiques, en passant au crible de grandes bibliothèques de peptides, est freiné par la nécessité d'utiliser un complexe radionucléide−chélateur qui peut affecter négativement les propriétés de liaison du peptide. Nous traitons ici de bibliothèques de peptides élaborées à l'aide de la méthode OBOC (une bille, un composé) et comportant le rhénium(I)tricarbonyl N-terminal, utilisées dans la sélection directe d'agents d'imagerie potentiels. Le rhénium(I) tricarbonyl est directement inséré dans la bibliothèque comme substitut d'élément d'imagerie pour rendre compte de la présence d'un chélate radionucléide de technétium-99m. L'identification de peptides organométalliques inconnus sur des billes séparées est réalisée avec succès au moyen de la MALDI couplée à la spectrométrie de masse, précédée d'une étude systématique des effets de différents chélates de rhénium(I) tricarbonyl N-terminal sur les schémas de fragmentation peptidique. [Traduit par la Rédaction]

Optimal His-Tag Design for Efficient [99mTc(CO)3]+ and [188Re(CO)3]+ Labeling of Proteins for Molecular Imaging and Radionuclide Therapy by Analysis of Peptide Arrays

“…Despite fragmentary investigation of the structures of protein adducts with [Re­(CO) 3 ] + , ,− little is known about the preferred amino acids or the coordination chemistry of the interactions. After evaluating the principle and methodology of use of a solid-phase peptide array for optimizing amino acid sequences for radiolabeling, a bespoke His-tag array was designed to optimize a His-tag-based sequence for efficient labeling with [ 99m Tc]­[Tc­(CO) 3 ] + , addressing a set of questions arising from both previously published data and results from the STKS-1 array described above: (1) Building on the observation (from STKS-1 array experiments) that a His residue is necessary but not sufficient for even moderately efficient labeling, what is the optimum number and arrangement of His residues, including interruption with other amino acids and embedding within a sequence ,, (rather than at the terminus)?…”

Incorporation of Fluorine into an OBOC Peptide Library by Copper-Free Click Chemistry toward the Discovery of PET Imaging Agents

“…The synthesis of one-bead one-compound (OBOC) libraries is a combinatorial method introduced by Lam et al in 1991 that involves split-and-mix synthesis to create millions of candidates from which peptide–receptor interactions can be discovered. Although the screening of classic OBOC libraries produces target-specific peptides, − post-identification modification of these peptides to convert them into imaging agents often decreases binding affinity and creates the necessity for further modifications. − However, few ventures have been made into making OBOC libraries of imaging agents. − …”