Our research on Peptide Nucleic Acids (abbreviated as PNAs) focuses on introducing chemical modifications that will make this class of molecules broadly useful to detect sequences of DNA and to suppress the progression of specific diseases. Unique DNA sequences are associated with diseases, pathogens, and many agents associated with bioterrorism. Detection of DNA from these agents can be employed as a method to detect their presence or absence. Our research involves the synthesis of a class of non-natural molecules (called PNAs) that bind to specific DNA sequences. We can design our molecules to bind to any sequence of DNA, and previously we have found that our molecules are extremely good at selective recognition of DNA associated with anthrax. During the past year, we have improved the chemistry to make our molecules, and have continued to refine our assay using our PNA molecules to detect as few as 60 copies of anthrax DNA. PNAs are also useful as antisense and antigene molecules, however delivery into cells has been difficult. We are starting a collaboration looking for specific delivery agents based on known bacterial proteins that help transport cargo into cells. Finally, we are exploring the potential of other PNAs as basic scaffolds for nanotechnology. Using a system of long DNA sequences, we are developing conditions for the self-assembly of specific PNAs onto DNA strands as a way to create nanopatters of specific biological ligands.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2010
Total Cost
$584,324
Indirect Cost
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State
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Tagad, Harichandra D; Debnath, Subrata; Clausse, Victor et al. (2018) Chemical Features Important for Activity in a Class of Inhibitors Targeting the Wip1 Flap Subdomain. ChemMedChem 13:894-901
Debnath, Subrata; Kosek, Dalibor; Tagad, Harichandra D et al. (2018) A trapped human PPM1A-phosphopeptide complex reveals structural features critical for regulation of PPM protein phosphatase activity. J Biol Chem 293:7993-8008
Liu, Yanning; Lou, Guohua; Norton, John T et al. (2017) 6-Methoxyethylamino-numonafide inhibits hepatocellular carcinoma xenograft growth as a single agent and in combination with sorafenib. FASEB J 31:5453-5465
Gupta, Pankaj; Rastede, Elizabeth E; Appella, Daniel H (2015) Multivalent LK?-PNA oligomers bind to a human telomere DNA G-rich sequence to form quadruplexes. Bioorg Med Chem Lett 25:4757-60
Gaynutdinov, Timur I; Englund, Ethan A; Appella, Daniel H et al. (2015) G-quadruplex formation between G-rich PNA and homologous sequences in oligonucleotides and supercoiled plasmid DNA. Nucleic Acid Ther 25:78-84
Dix, Andrew V; Conroy, Jennie L; George Rosenker, Kara M et al. (2015) PNA-Based Multivalent Scaffolds Activate the Dopamine D2 Receptor. ACS Med Chem Lett 6:425-9
Zhao, Chao; Hoppe, Travis; Setty, Mohan Kumar Haleyur Giri et al. (2014) Quantification of plasma HIV RNA using chemically engineered peptide nucleic acids. Nat Commun 5:5079
Englund, Ethan A; Zhang, Ning; Appella, Daniel H (2014) Cyclopentane peptide nucleic acids. Methods Mol Biol 1050:13-8
Englund, Ethan A; Gupta, Pankaj; Micklitsch, Christopher M et al. (2014) PPG peptide nucleic acids that promote DNA guanine quadruplexes. Chembiochem 15:1887-90
Dix, Andrew V; Moss, Steven M; Phan, Khai et al. (2014) Programmable nanoscaffolds that control ligand display to a G-protein-coupled receptor in membranes to allow dissection of multivalent effects. J Am Chem Soc 136:12296-303

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