Poster Presentation 11th Annual Conference of the International Chemical Biology Society 2022

Structural differences (cyclic versus linear) affect the activity of DNA-binding pyrrole−imidazole polyamides (#134)

Yuki Hirose 1 , Huy N. Hoang 2 , Toshikazu Bando 1 , Hiroshi Sugiyama 3 , David P. Fairlie 2
  1. Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan
  2. Division of Chemistry and Structural Biology and ARC Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  3. Institute for Integrated Cell-Material Science (WPI-iCeMS), Kyoto University, Kyoto, Japan

The genetic information contained in DNA is transcribed into mRNA, which is then translated into proteins. These processes define life, and abnormalities can cause a variety of diseases. Molecules that can bind tightly to DNA have the potential to be used as regulators of the expression of disease-associated genes and diagnostic probes. Pyrrole−Imidazole Polyamides (PIPs) are a class of DNA-binding oligopeptides, which are mainly composed of N-methylpyrrole (Py) and N-methylimidazole (Im) connected by amide bonds. Based on a unique recognition rule, PIPs bind to the minor groove of DNA in a sequence-specific manner. Antiparallel pairing of Im and Py recognizes a G/C base pair, whereas an antiparallel pair Py/Py recognizes an A/T or T/A base pair. Taking advantage of their high binding affinity and sequence-specificity, we can design PIPs to bind to different sequences and act as inhibitors/activators of gene transcription, and as fluorescent probes for specific sequences.1, 2

A γ-aminobutyric acid turn (γ-turn) can connect two arrangements of Py and Im and create two architectures of PIPs: hairpin3 and cyclic4 PIPs (hPIPs and cPIPs). hPIPs have been mainly used so far, while cPIPs have been less studied. However, because cPIPs have been shown with high affinity and specificity for some DNA sequences,4–6 a better understanding of their properties may help development of even more potent and specific gene regulators.

In this study, we evaluated and compared a cPIP and hPIP for properties such as DNA binding, gene regulation in cells, and cellular uptake. Further, we are investigating factors that cause differences in these properties by analyzing their structures in solution. Details of results obtained to date will be presented here.

  1. P. B. Dervan, B. S. Edelson, Curr. Opin. Struct. Biol. 2003, 13, 284–299.
  2. Y. Kawamoto, T. Bando, H. Sugiyama, Bioorg. Med. Chem. 2018, 26, 1393–1411.
  3. M. M. Mrksich, M. E. Parks, P. B. Dervan, J. Am. Chem. Soc. 1994, 116, 7983–7988.
  4. D. M. Herman, J. M. Turner, E. E. Baird, P. B. Dervan, J. Am. Chem. Soc. 1999, 121, 1121–1129.
  5. Y. Hirose, S. Asamitsu, T. Bando, H. Sugiyama, J. Am. Chem. Soc. 2019, 141, 13165–13170.
  6. Y. Hirose, T. Ohno, S. Asamitsu, K. Hashiya, T. Bando, H. Sugiyama, ChemBioChem 2022, 23, e202100533.