Drug Repositioning and Pharmacophore Identification in the Discovery of Hookworm MIF Inhibitors

作者：Cho Yoonsang; Vermeire Jon J; Merkel Jane S; Leng Lin; Du Xin; Bucala Richard; Cappello Michael^*; Lolis Elias

来源：Chemistry & Biology, 2011, 18(9): 1089-1101.

DOI：10.1016/j.chembiol.2011.07.011

The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new pharmacophores. Hookworms are blood-feeding, intestinal nematode parasites that infect up to 600 million people worldwide. Vaccination with recombinant Ancylostoma ceylanicum macrophage migration inhibitory factor (rAceMIF) provided partial protection from disease, thus establishing a "proof-of-concept" for targeting AceMIF to prevent or treat infection. A high-throughput screen (HTS) against rAceMIF identified six AceMIF-specific inhibitors. A nonsteroidal anti-inflammatory drug (NSAID), sodium meclofenamate, could be tested in an animal model to assess the therapeutic efficacy in treating hookworm disease. Furosemide, an FDA-approved diuretic, exhibited submicromolar inhibition of rAceMIF tautomerase activity. Structure-activity relationships of a pharmacophore based on furosemide included one analog that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity.

• 出版日期2011-9-23