Decaprenyl diphosphate synthase inhibitors activate gamma delta T cells

MEDI 105

Fenglin Yin, fyin@uiuc.edu1, Yonghui Zhang, yhzhang@uiuc.edu2, Rong Cao, rongcao@chad.scs.uiuc.edu3, Craig T Morita4, and Eric Oldfield, eo@chad.scs.uiuc.edu2. (1) Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, (2) Department of Chemistry, University of Illinois at Urbana-Champaign, 600S. Mathews Ave., Urbana, IL 61801, (3) Center for biophysics and computational biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, (4) Department of Internal Medicine and the Interdisciplinary Group in Immunology, University of Iowa, EMRB 340F, Iowa City, IA 52242
Gamma delta T cells play an important role in innate immunity since they represent a first of line defense against various pathogens, as well as being involved in tumor cell killing. Bisphosphonates show moderate activity in gamma delta T cell activation, due to inhibition of the enzyme farnesyl diphosphate synthase (FPPS), resulting in accumulation of isopentenyl diphosphate (IPP), a major diphosphate “phosphoantigen”. A much larger effect might be expected if other enzymes, which utilize larger amounts of IPP, are inhibited. The enzyme decaprenyl pyrophosphate synthase (DPPS) makes a C50 prenyl diphosphate precursor for ubiquinone biosynthesis by condensing seven IPP molecules to FPP. We synthesized a series of novel bisphophonates and tested them against the human DPPS enzyme. The bisphosphonates having potent activity against DPPS were found to be exceptionally active in T cell activation, indicating a new drug target for use in immunotherapy.
 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007