Organic Letters
Letter
expression of CXCR7 as well as CXCR4 in A549 cells,19,20 our
results indicate that amantamide (1) would be able to serve as
a selective agonist to help decipher the biological role of
CXCR7 in different disease models.
Information for details). However, ligand-displacement assays
and mutational studies would be necessary to validate the
binding mode of amantamide (1) with CXCR7.
In summary, we isolated amantamide (1), a new marine
cyanobacterial natural product, synthesized the compound, and
characterized it as a new CXCR7 agonist with confirmed
cellular activity. SAR studies to produce a diverse amantamide
analogue library and optimize the agonistic activity of
amantamide is ongoing. The selective activation of CXCR7
by 1 could provide the basis for developing CXCR7-targeted
therapeutics and deciphering the biological role of CXCR7
without interference with CXCR4.
To decipher the molecular interaction of amantamide (1)
against CXCR7, molecular modeling experiments were
performed. Brintonamide D was also identified as a CXCR7
agonist (EC50 3.97 μM), although it is a more potent CCR10
antagonist,9 so it was also included in the modeling process.
The sequence of CXCR7 protein was retrieved from UniProt
Knowledge Base with 362 residues.20 Due to lack of available
CXCR7 protein structure in the Protein Data Bank,21 we
developed a homology 3D model template for molecular
docking. Compared to a previous homology model published
by Montpas et al.,22 we expect our models be more reliable
because they possess much lower E values and the aligned
details). The docking results (Figures 5 and S13) indicate the
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
Experimental procedures, spectral data, and biological
investigation results (PDF)
AUTHOR INFORMATION
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Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We acknowledge financial support from the National Institutes
of Health, NCI Grant No. R01CA172310, the Debbie and
Sylvia DeSantis Chair professorship (H.L.), and Shenzhen
Peacock Plan (KQTD2015071714043444); M.A.R. acknowl-
edges Dr. Lydia E. Kavraki and Dr. Mark Moll (Department of
Computer Science, Rice University, Houston, TX) for
providing the DINC program for peptide docking.
REFERENCES
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Figure 5. Top view (A) and side view (B) of the binding sites with
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