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, and we have optimized this protocol for highly sensitive detection of HIV from plasma. 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, such as targeting G-coupled protein receptors.

Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2013
Total Cost
$932,673
Indirect Cost
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State
Country
Zip Code
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
Gupta, Pankaj; Rastede, Elizabeth E; Appella, Daniel H (2015) Multivalent (L)Kγ-PNA oligomers bind to a human telomere DNA G-rich sequence to form quadruplexes. Bioorg Med Chem Lett :
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
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
Englund, Ethan A; Zhang, Ning; Appella, Daniel H (2014) Cyclopentane peptide nucleic acids. Methods Mol Biol 1050:13-8
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
Macadangdang, Benjamin; Zhang, Ning; Lund, Paul E et al. (2011) Inhibition of multidrug resistance by SV40 pseudovirion delivery of an antigene peptide nucleic acid (PNA) in cultured cells. PLoS One 6:e17981
Onyshchenko, Mykola I; Gaynutdinov, Timur I; Englund, Ethan A et al. (2011) Quadruplex formation is necessary for stable PNA invasion into duplex DNA of BCL2 promoter region. Nucleic Acids Res 39:7114-23
Zhang, Ning; Appella, Daniel H (2010) Advantages of peptide nucleic acids as diagnostic platforms for detection of nucleic acids in resource-limited settings. J Infect Dis 201 Suppl 1:S42-5
Norton, John T; Witschi, Mark A; Luong, Lynn et al. (2008) Synthesis and anticancer activities of 6-amino amonafide derivatives. Anticancer Drugs 19:23-36