Jonathan W. Neidigh, PhD

Research Group Page

Research Summary

The Neidigh laboratory studies the mechanism whereby nucleoside analogs will inhibit the growth of cancer cells. Laboratory projects are focused on the metabolic activation and incorporation into DNA of compounds that either inhibit DNA replication or modify the expression of genes. Researchers in the Neidigh laboratory use a variety of powerful experimental and computation tools including molecular modeling, mass spectroscopy, and nuclear magnetic resonance (NMR) to address questions concerning the relationship between the chemical structure of drugs and their biological function.

The Neidigh laboratory is focused on two active projects, which examine the mechanism of action of drugs used clinically to treat human cancers. The first project uses mass spectrometry techniques to quantitatively examining the activation to the triphosphate analog, incorporation into DNA, and inhibition of DNA methylation of three potential cancer compounds, decitabine, zebularine, and 5-fluoro-2'-deoxycytidine. The second project examines the relationship between the 3D structure of gemcitabine and its in vivo mechanism of action including its phosphorylation by deoxycytidine kinase, incorporation into DNA by polymerases, and inhibition of polymerase activity. This project uses 2D NMR spectroscopy and computational methods to better understand how the chemical structure of gemcitabine inhibits cell growth. The results of these two studies should allow scientists to develop other, more effective agents for the treatment of human cancers.

Selected Publications

"Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase" S. Holder, M. Zemskova, C. Zhang, M. Tabrisisad, R. Bremer, J. W. Neidigh, and M. B. Lilly. Molecular Cancer Therapeutics 6, 163 - 172 (2007).

"Impact of cytosine 5-halogens on the interaction of DNA with restriction endonucleases and methyltransferase" V. Valinluck, W. Wu, P. Liu, J. W. Neidigh, and L. C. Sowers. Chemical Research in Toxicology 19, 556 - 562 (2006)

"Detection of DNA adducts derived from the reactive metabolite of furan, cis-2-butene-1,4-dial" M. C. Byrns, C. C. Vu, J. W. Neidigh, J. L. Abad, R. A. Jones, and L. A. Peterson. Chemical Research in Toxicology 19, 414 - 420 (2006).

“Peptide Conformational Changes Induced by Trptophan-Phosphocholine Interactions in a Micelle” J. W. Neidigh and N. H. Andersen. Biopolymers 65, 354 -361 (2002).

“Designing a 20 Residue Protein” J. W. Neidigh, R. M. Fesinmeyer, and N. H. Andersen. Nature Structural Biology 9, 425 – 430 (2002).

“Medium-Dependence of the Secondary Structure of Exendin-4 and Glucagon-like-peptide-1” N. H. Andersen, Y. Brodsky, J. W. Neidigh, and K. S. Prickett. Bioorganic & Medicinal Chemistry 10, 79 – 85 (2002).

“Exendin-4 and Glucagon-like-peptide-1: NMR Structural Comparisons in the Solution and Micelle-Associated States ” J. W. Neidigh, R. M. Fesinmeyer, K. S. Prickett, and N. H. Andersen. Biochemistry 40, 13188 – 13200 (2001).

“Effect of Hexafluoroisopropanol on the Thermodynamics of Peptide Secondary Structure Formation” N. H. Andersen, R. B. Dyer, R. M. Fesinmeyer, F. Gai, Z. Liu, J. W. Neidigh, and H. Tong. Journal of the American Chemical Society 121, 9879-9880 (1999).

"Extracting Information from the Temperature Gradients of Polypeptide NH Chemical Shifts: I. The Importance of Conformational Averaging," N. H. Andersen, J. W. Neidigh, S. M. Harris, G. M. Lee, Z. Liu, and H. Tong. Journal of the American Chemical Society 119, 8547-8561 (1997).