Associate Professor
Ph.D., University of Michigan
Biomolecular and medicinal chemistry of nucleic acids

Our research focuses on investigating and developing novel
RNA-targeted medicinal agents to potentially treat diseases such as HIV (the causative agent of AIDS); multidrug resistant bacterial infections; as well as cancer. RNA plays a critical role in viral replication, bacterial regulation and cancer biogenesis in addition to its role in normal cellular processes. Through structural biology and medicinal chemistry studies we are determining the structure-function relationships of novel RNA targets and the structure-activity relationships of medicinal agents that target the RNA. We utilize a multidisciplinary approach encompassing biophysical (primarily NMR), bioorganic, bioinformatic and molecular biology techniques to gain an in-depth understanding of the solution structure of the RNA targets and the factors that govern molecular recognition of the RNA by small molecules.

RNA STRUCTURAL BIOLOGY : Elegance in simple complexity

Through the varied arrangement of primarily four simple monomer units, a myriad of RNA structures and conformations can be accessed. Despite this potential for structural complexity, small RNA structural motifs often retain their native tertiary structure even when studied out of context of the full length RNA. By studying the structure-function relationships of these smaller motifs individually, one can gain valuable structural insight that can ultimately be used to connect together smaller motifs to obtain the structure of a larger unit, much like quilt blocks can be stitched together to make a large quilt. Our focus is on determining the solution structure of medicinally relevant RNA targets --RNA motifs that are critical for function in a diseased state. We utilize extensive NMR studies (at 800, 600 & 500 MHz) in addition to supplementary information from fluorescence, UV and CD studies. Through molecular modeling we are able to build a detailed picture of the RNA target that can ultimately be used in the rational drug design of novel medicinal agents as well as to gain a better insight into the functional role of the RNA.

RNA MEDICINAL CHEMISTRY : A new frontier in drug design

RNA-targeted drug design is a relatively new field of study. The challenge of obtaining detailed structural information of medicinally relevant RNA motifs has, in the past, been a barrier to detailed medicinal chemistry studies as has the lack of information regarding structure-activity relationships (SAR) of RNA-ligand interactions. Our research focuses on conducting detailed SAR studies of RNA binding ligands in order to gain better insight into the factors that govern molecular recognition of RNA by small molecules. In addition, we are using computational and bioinformatic approaches to create informational databases that can ultimately be used in the rapid drug screening of combinatorial libraries by NMR or in ribonomic studies of RNA arrays.

T box riboswitch antiterminator affinity modulated by tRNA structural elements J. A. Means, S. Wolf, A. Agyeman, J. S. Burton, C.M. Simson, J. V. Hines Chem. Biol. Drug Des., 2007, 69, 139-145.

Compositions that bind antiterminator RNA and assay for screening such compounds U.S. Patent Application, Serial No. 10/226,614; Awarded 2006.
 
Structure activity studies of oxazolidinone analogs as RNA-binding agents J. Means, S. Katz, A. Nayek, R.Anupam, J. V. Hines, S. C. Bergmeier Bioorg. Med. Chem. Letters, 2006, 16, 3600-3604.

In Virto Selection to Identify Determinants in tRNA for Bacillus tyrS T Box Antiterminator mRNA Binding. H. Fauzi, K.D.Jack, J.V. Hines, Nucleic Acids Res. 2005, 8, 2595-2602.

Flourescence resonance energy transfer studies of aminoglycoside binding to a T box antiterminator RNA.  J.A. Means, J.V. Hines, Bioorg. Med. Chem. Letters 2005, 15, 2169-2172.

Solution Structure of the B. subtilis T Box Antiterminator RNA: Seven-nucleotide bulge characterized by order and disorder. M.S. Gerdeman, T.M. Henkin, J.V. Hines, J. Mol. Biol., 2003 326,189-201.

Synthesis and Hybridization Studies of a 5-Aminopentanoic Acid Nucleobase (APN) Dimer S.F. Donaldson, S.C. Bergmeier, J.V. Hines, M. Gerdeman, Nucleosides, Nucleotides and Nucleic Acids, 2002 , 21, 111-123.

In Vitro Structure-Function Studies of the Bacillus subtilis tyrS mRNA Antiterminator: Evidence for factor-independent tRNA acceptor stem binding specificity. M.S. Gerdeman, T.M. Henkin, J.V. Hines, Nucleic Acids Res., 2002 , 30, 1065-1072.

T1 Measurements in Cell Cultures: A New Tool for Characterizing Contrast Agents at 1.5 T P. Schmalbrock, S.-M. Lee, J.V. Hines G. Ammar, E. W.-C. Kwok J. Magn. Reson. Imaging 2001 , 14, 636-648.