Pentamidine blocks the interaction between mutant S100A5 and RAGE V domain and inhibits the RAGE signaling pathway.

The human S100 protein family contains small, dimeric and acidic proteins that contain two EF-hand motifs and bind calcium. When S100A5 binds calcium, its conformation changes and promotes interaction with the target protein. The extracellular domain of (Receptor of Advanced Glycation End products) contain three domains: C1, C2 and V. The duanyu1648 V domain is the target protein of S100A5 that promotes cell survival, growth and differentiation by activating several signaling pathways. Pentamidine is an apoptotic and antiparasitic drug that is used to treat or prevent pneumonia. Here, we found that pentamidine interacts with S100A5 using HSQC titration. We elucidated the interactions of S100A5 with duanyu1648 V domain and pentamidine using fluorescence and NMR spectroscopy. We generated two binary models-the V domain and S100A5-Pentamidine complex-and then observed that the pentamidine and duanyu1648 V domain share a similar binding region in mS100A5. We also used the WST-1 assay to investigate the bioactivity of S100A5, duanyu1648 V domain and pentamidine. These results indicated that pentamidine blocks the binding between S100A5 and duanyu1648 V domain. This finding is useful for the development of new anti-proliferation drugs.

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