Both coding and non-coding DNA genomic sequences as well as their functional significance are becoming increasingly available. Modulating the functions of these sequences with sequence-specific, cell-permeable synthetic compounds would be extremely valuable. Deficiency of satisfactory synthetic compounds is a barrier to applications of our genomic knowledge in biotechnology and drug development. The project described herein will remove that barrier and will have an impact on human health through the potential for new anticancer and antiparasitic drugs as well as new biotechnology applications. The project builds on very successful results in our initial funding period. We found that it is possible to rationally design and prepare novel modules for both AT and GC base pair (BP) recognition in target DNA sequences. For the first time we have designed several new heterocyclic, cationic modules which selectively and strongly recognize a single GC bp with flanking AT sequences. This was a primary goal of our initial proposal and what we propose here builds from that success. Our design research was initiated with classical types of cell permeable AT specific minor groove binders that are based on a molecular platform that includes clinically useful compounds. Our target compounds maintain these features while incorporating new GC recognition modules. The downfall of most minor groove binders in therapeutics has been lack of sufficient cell and nuclear permeability. Our new compounds escaped this block but since we wish to target diseases from those induced by cancer to microorganisms, in Aim 1 we will continue to design, prepare and test new sequence-specific modules for cell permeability and biological activity.
Aim 2 of the proposal describes the preparation of entirely new types of mixed sequence recognition compounds with our established modules from Aim 1 linked by both serial and parallel methods to bind tightly and specifically to a broad array of mixed DNA sequences. Preliminary biophysical findings from our first funding period are a proof of concept that our linked modular design approach works and can be expanded to more complex sequences in the next funding period. A broad array of biophysical studies are performed on the new compound-DNA complexes including high resolution NMR methods and crystallography.
Aim 3 is entirely new and was not a part of our initial proposal. It builds on exciting preliminary results that illustrate important biological functions of our designed compounds. As a test system, collaborative results with the PU.1 transcription factor (TF) showed that new minor groove agents, identified in our biosensor in vitro assay, enter cells and nuclei and allosterically inhibit major groove binding TFs. This important result for future development of an array of TF inhibitors lead to collaborative evaluation of our compounds against low PU.1 acute myeloid leukemia (AML) patient cells. The compounds entered the cell and nuclei with selective PU.1 inhibition and AML cell death with no toxicity to cells to normal PU.1 cells. These results are the basis for Aim 3 with significant impact and major relevance for new drug development.

Public Health Relevance

This project will result in the design and development of new synthetic compounds for sequence-specific recognition of genomic DNA. These new reagents will be tailored to inhibit certain DNA transcription factor proteins linked to human disease. Successful targeting and inhibition of transcription factors involved in prostate cancer and in acute myeloid leukemia has been accomplished.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM111749-06
Application #
9618220
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sakalian, Michael
Project Start
2014-08-01
Project End
2022-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Georgia State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Farahat, Abdelbasset A; Ismail, Mohamed A; Kumar, Arvind et al. (2018) Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity. Eur J Med Chem 143:1590-1596
Mizuta, R; Devos, J M; Webster, J et al. (2018) Dynamic self-assembly of DNA minor groove-binding ligand DB921 into nanotubes triggered by an alkali halide. Nanoscale 10:5550-5558
Simone, Roberto; Balendra, Rubika; Moens, Thomas G et al. (2018) G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. EMBO Mol Med 10:22-31
Harika, Narinder K; Germann, Markus W; Wilson, W David (2017) First Structure of a Designed Minor Groove Binding Heterocyclic Cation that Specifically Recognizes Mixed DNA Base Pair Sequences. Chemistry 23:17612-17620
Antony-Debré, Iléana; Paul, Ananya; Leite, Joana et al. (2017) Pharmacological inhibition of the transcription factor PU.1 in leukemia. J Clin Invest 127:4297-4313
Paul, Ananya; Kumar, Arvind; Nanjunda, Rupesh et al. (2017) Systematic synthetic and biophysical development of mixed sequence DNA binding agents. Org Biomol Chem 15:827-835
Pett, Luke; Kiakos, Konstantinos; Satam, Vijay et al. (2017) Modulation of topoisomerase II? expression and chemosensitivity through targeted inhibition of NF-Y:DNA binding by a diamino p-anisyl-benzimidazole (Hx) polyamide. Biochim Biophys Acta Gene Regul Mech 1860:617-629
Guo, Pu; Paul, Ananya; Kumar, Arvind et al. (2017) A modular design for minor groove binding and recognition of mixed base pair sequences of DNA. Chem Commun (Camb) 53:10406-10409
Vo, Tam; Wang, Shuo; Poon, Gregory M K et al. (2017) Electrostatic control of DNA intersegmental translocation by the ETS transcription factor ETV6. J Biol Chem 292:13187-13196
Hong, Mei; Ren, Ming-Qiang; Silva, Jeane et al. (2017) YM155 inhibits topoisomerase function. Anticancer Drugs 28:142-152

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