Platform of oligonucleotide therapeutics discovery

Our drug discovery platform consists of following basic technologies accumulated in Professor Obika’s laboratory (Osaka University Graduate School of Pharmaceutical Sciences, Bioorganic Chemistry).

1. Bridged nucleic acids

There are three different bridged nucleic acids.

Modification of XNAs:Best material group for antisense applications

AmNA

AmNA

  • Improvement of nuclease resistance
  • Improvement of base-specific hybrid
  • Reduction in hepatotoxicity
  • Establishment of a basic production method for monomers
GuNA

GuNA

  • Improvement of nuclease resistance
  • Improvement of base-specific hybrid
  • Improvement of cell internalization (by positive charge in the structure)
scpBNA

scpBNA

  • Improvement of nuclease resistance
  • Improvement of base-specific hybrid
  • Reduction in hepatotoxicity
  • Add hydrophobicity in the sequence

Hepatotoxicity risks significantly decreased
compared to the earlier LNA technology.
+
Various oligonucleotide therapeutics with
different characteristics.

Comparison with other modifications: Our modification group endows your oligonucleotides with superior properties.

Modification Type Hybridize Nuclease resistance Hepatotoxicity Mfg. Cost
PS DNA   + +++++ ++ +
2′-OMe 2′-modify ++ + ++
2′-F 2′-modify ++ + ++ ++
2′-MOE 2′-modify ++ ++ + +++
LNA Bi-cyclic ++++ ++ +++++
(Hepatotoxicity)
++++
S-cEt Bi-cyclic ++++ +++ + +++++++
AmNA Bi-cyclic ++++ +++ + +++
GuNA Bi-cyclic ++++ ++++ + ++++
scpBNA Bi-cyclic ++++ +++++ + ++++

Our modification

References

  • AmNA

    Yahara A1, Shrestha AR, Yamamoto T, Hari Y, Osawa T, Yamaguchi M, Nishida M, Kodama T, Obika S.
    Amido-bridged nucleic acids (AmNAs): synthesis, duplex stability, nuclease resistance, and in vitro antisense potency.
    Chembiochem. 2012 Nov 26;13(17):2513-6

    Yamamoto T1, Yahara A, Waki R, Yasuhara H, Wada F, Harada-Shiba M, Obika S.
    Amido-bridged nucleic acids with small hydrophobic residues enhance hepatic tropism of antisense oligonucleotides in vivo.
    Org Biomol Chem. 2015 Mar 28;13(12):3757-65

    Setoguchi K, Cui L, Hachisuka N, Obchoei S, Shinkai K, Hyodo F, Kato K, Wada F, Yamamoto T, Harada-Shiba M, Obika S, Nakano K.
    Antisense Oligonucleotides Targeting Y-Box Binding Protein-1 Inhibit Tumor Angiogenesis by Downregulating Bcl-xL-VEGFR2/-Tie Axes.
    Mol Ther Nucleic Acids. 2017 Dec 15;9:170-181

  • GuNA

    Shrestha AR1, Kotobuki Y, Hari Y, Obika S.
    Guanidine bridged nucleic acid (GuNA): an effect of a cationic bridged nucleic acid on DNA binding affinity.
    Chem Commun (Camb). 2014 Jan 18;50(5):575-7

    Horie N, Kumagai S, Kotobuki Y, Yamaguchi T, Obika S.
    Facile synthesis and fundamental properties of an N-methylguanidine-bridged nucleic acid (GuNA[NMe]).
    Org Biomol Chem. 2018 Sep 11;16(35):6531-6536.

  • scpBNA

    Horiba M, Yamaguchi T, Obika S.
    Synthesis of scpBNA-mC, -A, and -G Monomers and Evaluation of the Binding Affinities of scpBNA-Modified Oligonucleotides toward Complementary ssRNA and ssDNA.
    J Org Chem. 2016 Nov 18;81(22):11000-11008.

    Yamaguchi T, Horiba M, Obika S.
    Synthesis and properties of 2′-O,4′-C-spirocyclopropylene bridged nucleic acid (scpBNA), an analogue of 2′,4′-BNA/LNA bearing a cyclopropane ring.
    Chem Commun (Camb). 2015 Jun 14;51(47):9737-40.

This research was found as a result of AMED’s Basic Science and Platform Technology Program for Innovative Biological Medicine.
Under an in-licensing agreement, Osaka University has granted us full and exclusive rights to their technology related to the bridged nucleic acid group.

2. Antisense toxicity reduction technology

Antisense drugs are associated with the risk of hepatotoxicity.
At Osaka University, they discovered that the following technologies reduce hepatotoxicity by utilizing a new bridged nucleic acid and/or base modification incorporated into the oligonucleotide, and furthermore, they are developing technologies aiming at minimizing hepatotoxicity.

  • 1)Base modification of gap segment in gapmer antisense oligonucleotide
  • 2)Dual modification of wing segment in gapmer antisense oligonucleotide

Under an in-licensing agreement, Osaka University has granted us full and exclusive rights to their technology related to the bridged nucleic acid group.

3. Sequence design system

It is important in the design process to decide in which mRNA area to develop antisense therapy.
Based on basic technologies accumulated in Osaka University and NIBIOHN, we are advancing our own research and setting up design technologies to obtain as many candidate sequences as we can.

Our platform of oligonucleotide therapeutics development

Advantages of our technologies

  • High affinity for targeted mRNA.
  • Superior safety due to reduced hepatotoxicity.
  • Possible to change site that oligonucleotide therapeutics can reach.
  • Able to design antisense sequence.

 

We utilize a basic technology group that enables us to develop oligonucleotide therapeutics with high safety, tolerability and effectiveness.

Under an in-licensing agreement, Osaka University has granted us full and exclusive rights to their technology.