Abstract 6417: High-throughput peptide screening for radioligands by DNA encoded libraries

Abstract Targeting ligands play a critical role in radiopharmaceuticals for cancer diagnosis and therapy. Due to their excellent binding affinity and specificity, peptides have been widely used to conjugate with radionuclides for delivery to cancer cells in targeted lesions. Current high-throughput de novo peptide hit finding heavily relies on phage display and mRNA display. While efficient, the generation of those peptide libraries is still limited by the biological translation process. As an emerging peptide screening approach, DNA encoded library technology (DELT) offers a higher degree of chemical flexibility. Unnatural amino acids and a variety of cyclization strategies that are inaccessible to display technologies can be readily incorporated into DEL peptides, leading to improved pharmacokinetic profiles including prolonged retention time and increased in vivo stability. Here we report our efforts in developing billion-member peptide libraries and primary screening for radioligand discovery through DELT, followed by high-throughput solid-phase synthesis that accelerates hit confirmation and affinity maturation. Citation Format: Yihui Xie. High-throughput peptide screening for radioligands by DNA encoded libraries [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6417.