Targeting SDF-1/CXCL12 with a ligand that prevents activation of CXCR4 through structure-based drug design
Christopher T Veldkamp1, Joshua J Ziarek, Francis C Peterson
1Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA.
Abstract:
CXCL12 is an attractive target for clinical therapy because of its involvement in autoimmune diseases, cancer growth, metastasis, and neovascularization. Tyrosine sulfation at three positions in the CXCR4 N-terminus is crucial for specific, high-affinity CXCL12 binding. An NMR structure of the complex between the CXCL12 dimer and a sulfotyrosine-containing CXCR4 fragment enabled high-throughput in silico screening for inhibitors of the chemokine-receptor interface. A total of 1.4 million compounds from the ZINC database were docked into a cleft on the CXCL12 surface normally occupied by sulfotyrosine 21 (sY21), and five were selected for experimental screening. NMR titrations with CXCL12 revealed that four of the compounds occupy the sY21 site, one of which binds with a K(d) of 64 microM. This compound selectively inhibits SDF1-induced CXCR4 signaling in THP1 cells. Our results suggest that sulfotyrosine recognition sites can be targeted for the development of novel chemokine inhibitors.
Insights
Researchers identified novel inhibitors targeting the CXCL12-CXCR4 interaction by screening millions of compounds. This discovery offers a new strategy for developing therapeutics for autoimmune diseases and cancer by targeting sulfotyrosine recognition sites.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- Chemokine CXCL12 (also known as SDF1) plays a critical role in autoimmune diseases, cancer metastasis, and neovascularization.
- High-affinity binding of CXCL12 to its receptor CXCR4 is dependent on tyrosine sulfation at the CXCR4 N-terminus.
- Targeting the CXCL12-CXCR4 interaction is a promising therapeutic strategy.
Purpose of the Study:
- To develop novel inhibitors of the CXCL12-CXCR4 chemokine-receptor interface.
- To identify compounds that specifically target the sulfotyrosine recognition site on CXCL12.
Main Methods:
- Utilized NMR structure of the CXCL12 dimer complexed with a sulfotyrosine-containing CXCR4 fragment.
- Performed high-throughput in silico screening of 1.4 million compounds from the ZINC database.
- Conducted NMR titrations to validate compound binding and experimental screening of selected compounds.
Main Results:
- Identified four compounds that bind to the sulfotyrosine 21 (sY21) site on CXCL12.
- One compound demonstrated binding with a K(d) of 64 microM.
- This lead compound selectively inhibited SDF1-induced CXCR4 signaling in THP1 cells.
Conclusions:
- Sulfotyrosine recognition sites represent viable targets for developing novel chemokine inhibitors.
- The identified compounds show potential for therapeutic development in CXCL12-mediated diseases.
- This study provides a foundation for structure-based drug design targeting chemokine-receptor interactions.
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