Development of a large peptoid–DOTA combinatorial library

Abstract

Conventional one-bead one-compound (OBOC) library synthesis is typically used to identify molecules with therapeutic value. The design and synthesis of OBOC libraries that contain molecules with imaging or even potentially therapeutic and diagnostic capacities (e.g. theranostic agents) has been overlooked. The development of a therapeutically active molecule with a built-in imaging component for a certain target is a daunting task, and structure-based rational design might not be the best approach. We hypothesize to develop a combinatorial library with potentially therapeutic and imaging components fused together in each molecule. Such molecules in the library can be used to screen, identify, and validate as direct theranostic candidates against targets of interest. As the first step in achieving that aim, we developed an on-bead library of 153,600 Peptoid-DOTA compounds in which the peptoids are the target-recognizing and potentially therapeutic components and the DOTA is the imaging component. We attached the DOTA scaffold to TentaGel beads using one of the four arms of DOTA, and we built a diversified 6-mer peptoid library on the remaining three arms. We evaluated both the synthesis and the mass spectrometric sequencing capacities of the test compounds and of the final library. The compounds displayed unique ionization patterns including direct breakages of the DOTA scaffold into two units, allowing clear decoding of the sequences. Our approach provides a facile synthesis method for the complete on-bead development of large peptidomimetic-DOTA libraries for screening against biological targets for the identification of potential theranostic agents in the future.

Bio-instructive materials on-demand – combinatorial chemistry of peptoids, foldamers, and beyond

“…The approach has shown to be suitable for peptoid syntheses up to several million compounds. 42,[77][78][79] . We applied the split-and-pool approach on the IRORI technology to perform a large-scale synthesis of certain peptoids.…”

Peptoids as tools and sensors

“…The 153 600‐member library of DOTA‐tripeptoids of Singh et al . was prepared as a resource for theranostic development, being a combination of a therapeutic peptoid tethered to an imaging DOTA/PET tracer metal complex.…”

The Scope of Application of Macrocyclic Polyamines Beyond Metal Chelation

“…Another approach was reported by Udugamasooriya and co‐workers in which they use DOTA to build on‐bead combinatorial libraries of DOTA‐peptoid conjugates, aimed at being used for screening and discovering novel and multivalent theranostic agents. To this end, one arm of the DOTA was used to immobilize the construct on TentaGel beads (300 µ m diameter) via a short Met‐(Nmea‐Gly)‐βAla linker [Met for methionine, Nmea‐Gly for N ‐(2‐methoxyethyl)glycine and βAla for β‐alanine], the three other arms used to introduce 6‐ mer peptoid units through PEG‐type linkers of various lengths (Figure ).…”