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 continued to refine our assay using our PNA molecules to detect as few as 60 copies of anthrax DNA and we explored the quantitative and qualitative regions of detection. We have also extended this strategy to detect HIV RNA. PNAs are also useful as antisense and antigene molecules, however delivery into cells has been difficult. We have a new collaboration looking for specific delivery agents based on known bacterial proteins that help transport cargo into cells. Finally, we also completed a study exploring the potential of other PNAs as basic scaffolds for nanotechnology. Using a system of long DNA sequences, we developed conditions for the self-assembly of specific PNAs onto DNA strands as a way to create nanopatterns of specific biological ligands and we have applied this to improve the efficacy of a small cyclic peptide (cRGD) for inhibition of cancer metastasis in a mouse model. We are now extending this system to other areas of multivalency in biology.

Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2012
Total Cost
$1,019,038
Indirect Cost
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State
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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
Englund, Ethan A; Zhang, Ning; Appella, Daniel H (2014) Cyclopentane peptide nucleic acids. Methods Mol Biol 1050:13-8
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; 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
Micklitsch, Christopher M; Oquare, Bereket Yemane; Zhao, Chao et al. (2013) Cyclopentane-peptide nucleic acids for qualitative, quantitative, and repetitive detection of nucleic acids. Anal Chem 85:251-7
Panyutin, Igor G; Onyshchenko, Mykola I; Englund, Ethan A et al. (2012) Targeting DNA G-quadruplex structures with peptide nucleic acids. Curr Pharm Des 18:1984-91
Englund, Ethan A; Wang, Deyun; Fujigaki, Hidetsugu et al. (2012) Programmable multivalent display of receptor ligands using peptide nucleic acid nanoscaffolds. Nat Commun 3:614

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