9MAP

Crystal structure of GAGWLP and PD-L1

Summary for 9MAP

• Entry DOI: 10.2210/pdb9map/pdb
• Descriptor: Programmed cell death 1 ligand 1, G-AGWLP, PHOSPHATE ION, ... (6 entities in total)
• Functional Keywords: pd-l1, g-agwlp, complex, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 17060.91

Authors

Yang, P.,Chen, M.R.,Xiao, Y.B. (deposition date: 2025-03-14, release date: 2025-12-03, Last modification date: 2026-04-08)

Primary citation

Cheng, X.,Jiang, S.,Peng, X.,Yang, P.,Zhang, S.,Xu, C.,Gao, X.,Fan, S.,Liu, H.,Zhuang, J.,Chen, X.,Liang, N.,Lin, B.,Lu, Q.,Chen, M.,Xiao, Y.,Zhu, Z.,Wang, R.,Hu, K.,Wu, C.
Multicyclic Peptides Targeting PD-L1 for Radiotheranostics: From Discovery to Clinical Proof-of-Concept.
J.Am.Chem.Soc., 147:35638-35654, 2025

PubMed Abstract: Radiotheranostics holds transformative potential for precision oncology by integrating diagnostic imaging with targeted radionuclide therapy. However, advancements in this field are significantly hindered by the limited availability of high-affinity ligands that are capable of engaging challenging cell-surface antigens, particularly flat, low-druggability targets such as programmed death-ligand 1 (PD-L1). Here, we overcome this barrier through de novo discovery and rational engineering of a disulfide-directed multicyclic peptide (DDMP), dmp10, which achieves a picomolar affinity for PD-L1 by leveraging conformationally constrained structural scaffolds. By combining disulfide-directed library design with iterative directed evolution, we successfully generated dmp10, a ∼3 kDa multicyclic peptide that establishes unprecedented shape complementarity to the expansive binding interface of PD-L1. Preclinical evaluations demonstrated that Ga-labeled dmp10 enables high-contrast PET imaging of PD-L1 tumors in murine models, achieving a tumor uptake of 13.27 %ID/g at 4 h post-injection. The therapeutic counterpart, Lu-labeled dmp10, effectively eradicated 92.47% of established tumors in tumor models while sparing healthy tissues, thereby validating its dual radiotheranostic utility. The translational relevance of our findings was further confirmed in a first-in-human pilot study, where Ga-labeled dmp10 was well tolerated and allowed visualization of PD-L1 lesions in patients with solid tumors. This work not only establishes DDMPs as a versatile platform for targeting geometrically complex antigens but also delivers a promising radiotheranostic agent that bridges molecular imaging and precision radionuclide therapy for PD-L1-driven malignancies. Our findings advance current strategies for designing ultrahigh-affinity peptide binders and underscore the untapped potential of multicyclic architectures in overcoming longstanding challenges in cancer theranostics.

PubMed: 40974147
DOI: 10.1021/jacs.5c11292

Experimental method

X-RAY DIFFRACTION (3 Å)