Researchers have synthesized a new series of small organic compounds that could inhibit the activity of macrophage migration inhibitory factor (MIF), a small protein molecule involved in aggravating diseases such as rheumatoid arthritis and cancer1. The organic compounds might yield therapies for MIF-mediated diseases.
MIF cells are expressed in response to infection. They trigger inflammation in diseases such as rheumatoid arthritis, atherosclerosis, diabetes, sepsis, cancer, colitis, inflammatory bowel disease, multiple sclerosis, asthma and inflammatory liver disease.
To find potential drug molecules that can inhibit MIF, the researchers prepared several organic compounds containing isoxazoline. They screened these compounds by developing human MIF (huMIF)-induced inflammation in a cellular model of mouse leukaemic monocyte macrophage cell line.
They found that compounds 1c, 3f and 4b were most active in inhibiting huMIF. Of these three compounds, the researchers found 4b to be the most potent. They tested this compound's ability to bind to huMIF and stop the translocation of nuclear factor-kappa B (NF-kB), a protein molecule known to activate small proinflammatory molecules. NF-kB is translocated to the nucleus by huMIF.
Compound 4b attached to huMIF through van der Waals attraction and hydrogen bond formation, and inhibited huMIF-mediated translocation of NF-kB. In studies with cultured mouse macrophage and gastric mucosal cells, the compound proved to be non-toxic. This compound, the researchers say, could be used to fight huMIF-induced proinflammatory diseases.
The authors of this work are from: Indian Institute of Chemical Biology and University of Calcutta, Kolkata and Department of Chemistry, University of Burdwan, West Bengal, India.