Development of a large peptoid-DOTA combinatorial library.
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. © 2016 The Authors. Biopolymers Published by Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 673-684, 2016.
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204.
Jaspal
J
Singh
Advanced Imaging Research Center, UT-Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390.
Daniel
D
Lopes
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204. gomika@uh.edu.|Department of Cancer Systems Imaging, MD Anderson Cancer Center, 1881 East Road, Houston, TX, 77030-4009. gomika@uh.edu.|Advanced Imaging Research Center, UT-Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390. gomika@uh.edu.|Department of Biochemistry, UT-Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390. gomika@uh.edu.
D
D
Gomika Udugamasooriya
D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D019151:Peptide Library; D034444:Peptoids / Q000737:chemistry*
D006573:Heterocyclic Compounds, 1-Ring; D019151:Peptide Library; D034444:Peptoids; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
DOTA; combinatorial; imaging; peptoids; theranostics