Nature-inspired small molecules for regulation of therapeutically important genes

• Project/Area Number: 26670055
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Kyoto University
• Principal Investigator: NAMASIVAYAM Ganesh Pandian 京都大学, 物質-細胞統合システム拠点, 助教 (20625446)
• Co-Investigator(Kenkyū-buntansha): SUGIYAMA Hiroshi 京都大学, 理学研究科, 教授 (50183843) ; BANDO Toshikazu 京都大学, 理学研究科, 准教授 (20345284)
• Project Period (FY): 2014-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 天然分子を模倣した化合物 / DNAベースの治療 / 遺伝子発現制御 / マルチターゲットな小分子化合物 / エピゲノム

Outline of Final Research Achievements

Synthetic transcriptional activators adept of therapeutic gene modulation could be harnessed for developing strategies to treat some uncured defect-transcriptional machinery associated disorders. We have successfully advanced distinct DNA-based epigenome-modulating small molecules as first-ever bio-inspired genetic switches for activating exclusive cluster of therapeutically important genes including those providing resistance towards ocular disorders and HIV. Also, an `ON` switch for miR-302 familial microRNAs and an `OFF` switch for EVI1 oncogene were developed. Integration of epigenetic modulators on synthetic DNA-based domain effectively activated genes associated pluripotency and cartilage development. Next-generation sequencing studies guided the construction of second-generation genetic switches. Our proof-of-concept studies validate the switchable roles of epigenetic enzymes in gene regulation and provide a molecular basis for developing versatile bioactive ligands.

Research Products

• [Journal Article] Integrating epigenetic modulators into NanoScript for enhanced chondrogenesis of stem cells (2015)
  • Author(s): S. Patel, T. Pongkulapa, P. Yin, Ganesh N. Pandian, C. Rathnam, T. Bando, T. Vaijayanthi, H. Sugiyama and K-B. Lee.
  • Journal Title: Journal of the American Chemical Society (ACS Publications) Volume: 137 Issue: 14 Pages: 4598-4601
  • DOI: 10.1021/ja511298n
  • Peer Reviewed
• [Journal Article] Advancing small-molecule-based chemical biology with next-generation sequencing technologies (2015)
  • Author(s): C. Anandhakumar, S. Kizaki, Ganesh N. Pandian, T. Bando, and H. Sugiyama.
  • Journal Title: ChemBioChem Volume: 16 Issue: 1 Pages: 20-38
  • DOI: 10.1002/cbic.201402556
  • NAID: 120006460115
  • Peer Reviewed
• [Journal Article] A synthetic transcriptional activator of genes associated with retina in human dermal fibroblasts (2015)
  • Author(s): J. Syed, C. Anandhakumar, Ganesh N. Pandian, J. Taniguchi, S. Sato, K. Hashiya, G. Kashiwazaki, T. Bando, and H. Sugiyama
  • Journal Title: ChemBioChem Volume: In press Issue: 10 Pages: 1497-1501
  • DOI: 10.1002/cbic.201500140
  • NAID: 120005670900
  • Peer Reviewed
• [Journal Article] Identification of a Small Molecule that Turns `ON` the Pluripotency Gene Circuitry in Human Fibroblasts. (2014)
  • Author(s): Pandian, G, N.; Sato, S.; Anandhakumar, C.; Taniguchi, J.; Takashima, K.; Syed, J; Han, L.; Saha, A.; Bando, T.; Nagase, H.; Sugiyama, H.
  • Journal Title: ACS Chem. Biol. Volume: 9 Issue: 12 Pages: 2729-2736
  • DOI: 10.1021/cb500724t
  • Peer Reviewed
• [Journal Article] Alteration of epigenetic program to recover memory and alleviate neurodegeneration: Prospects of multi-target molecules (2014)
  • Author(s): Ganesh N. Pandian, R. D. Taylor, S. Junetha, A. Saha, C. Anandhakumar, T. Vaijayanthi, and H. Sugiyama.
  • Journal Title: Biomaterials Science - Royal Society of Chemistry Volume: 2 Issue: 8 Pages: 1043-1056
  • DOI: 10.1039/c4bm00068d
  • NAID: 120005625644
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Chemical Modification of a Synthetic Small Molecule Boosts its Biological Efficacy against Pluripotency Genes in Mouse Fibroblast. (2014)
  • Author(s): Saha, A.; Pandian, G. N.; Sato, S.; Taniguchi, J.; Kawamoto, Y.; Hashiya, K.; Bando, T.; Sugiyama, H.
  • Journal Title: ChemMedChem Volume: 9 Issue: 10 Pages: 2374-2380
  • DOI: 10.1002/cmdc.201402117
  • NAID: 120005657928
  • Peer Reviewed
• [Journal Article] Targeted Suppression of EVI1 Oncogene Expression by Sequence-Specific Pyrrole-imidazole Polyamide (2014)
  • Author(s): Junetha, S.; Pandian, G, N.; Sato, S.; Taniguchi, J.; Anandhakumar, C.; Hashiya, K.; Bando, T.; Sugiyama, H.
  • Journal Title: Chem. Biol. Volume: 23 Issue: 10 Pages: 1370-1380
  • DOI: 10.1016/j.chembiol.2014.07.019
  • NAID: 120005512270
  • Peer Reviewed
• [Journal Article] Next-Generation Sequencing Studies Guide the Design of Pyrrole-Imidazole Polyamides with Improved Binding Specifictiy by the Addition of β-alanine. (2014)
  • Author(s): Anandhakumar, C.; Li, Y.; Kizaki, S.; Pandian, G. N.; Hashiya, K.; Bando, T.; Sugiyama, H.
  • Journal Title: ChemBioChem Volume: 15 Issue: 18 Pages: 2647-2651
  • DOI: 10.1002/cbic.201402497
  • Peer Reviewed
• [Presentation] Therapeutic gene modulation using DNA-based transcriptional activators (2015)
  • Author(s): Ganesh N. Pandian, J. Taniguchi, S. Sato, L. Han, S. Junetha, T. Bando, and H. Sugiyama
  • Organizer: Asian International Symposium -Medicinal Chemistry in The 95th Annual Meeting of The Chemical Society of Japan
  • Place of Presentation: Funabashi, Chiba, Japan
  • Year and Date: 2015-03-26 – 2015-03-29
  • Invited
• [Presentation] Alteration of global gene expression in human somatic cells using DNA-based epigenetic switches (2014)
  • Author(s): Ganesh N. Pandian, J. Taniguchi, S. Junetha, S. Sato, L. Han, A. Saha, C. Anandhakumar, T. Bando, and H. Sugiyama
  • Organizer: ISSCR Regional Forum - Global control of stem cells
  • Place of Presentation: Biopolis, Singapore
  • Year and Date: 2014-11-05 – 2014-11-07
• [Book] Chapter 2 Synthetic strategies to identify and regulate noncoding RNAs in Long Noncoding RNAs: Structures and Functions (2015)
  • Author(s): Ganesh N. Pandian, J. Syed, and H. Sugiyama
  • Total Pages: 224
  • Publisher: Springer Japan, Editors: Kurokawa, Riki
• [Remarks] INSIDE COVER in Biomaterials Science
  • URL: http://pubs.rsc.org/en/content/articlelanding/2014/bm/c4bm90023e#!divAbstract