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Brian Wasko


brian-wasko@uiowa.edu
Mentor: Raymond Hohl, M.D./Ph.D.
Lab Room: 5219 MERF
Lab Phone: 319-335-8272

Inhibition of the Isoprenoid Biosynthetic Pathway by Novel Bisphosphonates

The isoprenoid biosynthetic pathway is responsible for the synthesis of a wide array of compounds with diverse biological functions. Products of the mammalian pathway include farnesyl pyrophosphate, geranylgeranyl pyrophosphate, ubiquinone, dolichol, and cholesterol. Inhibition of enzymes within the human pathway has proven to be clinically relevant. The statins are used widely for treatment of hypercholesterolemia and function by inhibiting HMG-CoA reductase, the rate limiting step in cholesterol synthesis. Clinical bisphosphonates are used for treatment of osteoporosis and metastatic bone disease and function by inhibiting farnesyl diphosphate synthase, resulting in depletion of the intracellular isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Our collaborators have synthesized numerous bisphosphonate analogs containing isoprene derived moieties as well as other substituents that have been shown by our laboratory to be capable of inhibiting human farnesyl diphosphate synthase and/or geranylgeranyl diphosphate synthase. The current focus of my research involves inhibition of human squalene synthase as well as a Mycobacterium tuberculosis prenyltransferase enzyme. Squalene synthase is of interest as it is responsible for the first committed step in cholesterol synthesis from farnesyl pyrophosphate. The mycobacterial prenyltransferase enzyme being targeted is involved in cell wall biosynthesis and is essential for viability of the microorganism. These enzymes, as well as others have been purified and in vitro assays have been utilized to identify potent novel inhibitors. Ongoing studies involve characterization of the lead compounds in relevant cellular models.

Wasko BM, Smits JP, Shull LW, Wiemer DF, Hohl RJ. A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro. J Lipid Res. 2011 Nov;52(11):1957-64. Epub 2011 Sep 8. PubMed PMID: 21903868; PubMed Central PMCID: PMC3196227.

Wasko BM, Dudakovic A, Hohl RJ. Bisphosphonates induce autophagy by depleting geranylgeranyl diphosphate. J Pharmacol Exp Ther. 2011 May;337(2):540-6. Epub 2011 Feb 18. PubMed PMID: 21335425.

Barney RJ, Wasko BM, Dudakovic A, Hohl RJ, Wiemer DF. Synthesis and biological evaluation of a series of aromatic bisphosphonates. Bioorg Med Chem. 2010 Oct 15;18(20):7212-20. Epub 2010 Aug 19. PubMed PMID: 20832326.

Wiemer AJ, Yu JS, Shull LW, Barney RJ, Wasko BM Lamb KM, Hohl RJ, Wiemer DF. Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation. Bioorg Med Chem. 2008 Apr 1;16(7):3652-60. Epub 2008 Feb 8. PubMed PMID: 18308574.