3D Modeling of a Natural Killer Receptor, Siglec-7: Critical Amino Acids for Glycan-Binding and Cell Death-Inducing Activity

Yamaji, Taiki; Yamaguchi, Yoshiki; Mitsuki, Motoaki; Takashima, Shou; Waguri, Satoshi; Hashimoto, Yasuhiro; Nara, Kiyomitsu

doi:10.5772/31157

Cited by 1 publication

(1 citation statement)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to Siglec-7, human NK cells also express the closely related receptor Siglec-9, albeit at lower expression levels (Figure A). ,− We therefore wanted to check for a possible cross-reaction of our Siglec-7 inhibitor with Siglec-9. The two proteins have 76% similarities in their ligand binding domain and display different ligand preferences only based on a six amino acid sequence. , These amino acids form in part the Tyr-64 cavity, and one might therefore predict selectivity of our ligands toward Siglec-7. However, we still wanted to experimentally explore the affinity of 32 to Siglec-9, because such an interaction might cause functional effects even in absence of any impact on Siglec-7 .…”

Section: Results and Discussionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Small, High-Affinity Siglec-7 Ligands: Toward Novel Inhibitors of Cancer Immune Evasion

Prescher

Frank

Gütgemann³

et al. 2017

J. Med. Chem.

View full text Add to dashboard Cite

Natural killer cells are able to directly lyse tumor cells, thereby participating in the immune surveillance against cancer. Unfortunately, many cancer cells use immune evasion strategies to avoid their eradication by the immune system. A prominent escape strategy of malignant cells is to camouflage themselves with Siglec-7 ligands, thereby recruiting the inhibitory receptor Siglec-7 expressed on the NK cell surface which subsequently inhibits NK-cell-mediated lysis. Here we describe the synthesis and evaluation of the first, high-affinity low molecular weight Siglec-7 ligands to interfere with cancer cell immune evasion. The compounds are Sialic acid derivatives and bind with low micromolar K values to Siglec-7. They display up to a 5000-fold enhanced affinity over the unmodified sialic acid scaffold αMe Neu5Ac, the smallest known natural Siglec-7 ligand. Our results provide a novel immuno-oncology strategy employing natural immunity in the fight against cancers, in particular blocking Siglec-7 with low molecular weight compounds.

show abstract