Abstract 5670: Using molecular docking to develop a novel peptide targeting tumor-associated macrophages based on RXRB recognition

Abstract Tumor-associated macrophages (TAMs) play a critical role in tumor progression, and thus have attracted great attention for therapeutic development. However, macrophage-modulating strategies suffer from drawbacks that they may interfere with normal immunity. Therefore, it is desirable to target and modulate macrophages in tumor-specific manner. We previously identified one such peptide, termed CRV, which selectively homes to a variety of solid tumors and bind TAMs within upon systemic administration. This TAM-targeting ability was then attributed to CRV receptor, retinoid X receptor beta (RXRB). While CRV demonstrated desirable properties in tumor homing and TAM recognition in vivo, the actual affinity to RXRB was very weak. We hypothesize that peptide variants with a higher affinity to RXRB may exhibit a more specific targeting of TAMs. To test this hypothesis, we employed molecular docking to optimize the CRV sequence. Seven rounds of optimization were carried out to replace one residue of CRV peptide in each round with nineteen other amino acids, and the binding energy was calculated as the selection criterion. This study identified a novel peptide, termed CRH, with an improved predicted binding affinity compared to CRV (-12.2 kcal/mol vs. -8.9 kcal/mol). In vitro assays verified that CRH possesses a higher affinity to RXRB than CRV. Ongoing studies include surface plasmon resonance (SPR) binding analysis and in vivo homing evaluations. Overall, we showcase here the identification of a novel peptide to target TAMs, which may enable a more precise drug delivery and TAM modulation. Citation Format: Nianwu Wang, Hong-Bo Pang. Using molecular docking to develop a novel peptide targeting tumor-associated macrophages based on RXRB recognition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5670.