Research

Medium-sized molecules such as peptides and nucleic acids are attracting attention as a new drug discovery modality following small molecule and macromolecular drugs, because they can be chemically synthesized and have the advantage of low production cost, in addition to being able to design biological activities that are difficult to achieve with small molecule drugs. However, there are still some major issues to be solved. We are aiming to overcome these issues by developing midium-sized molecules that are active only in specific environments, such as diseased cells, through the use of structural transformation from cyclic to linear structures.
 
References:
• H. Kitagawa, M. Kikuchi, S. Sato, H. Watanabe, N. Umezawa, M. Kato, Y. Hisamatsu, T. Umehara, T. Higuchi, "Structure-based identification of potent lysine-specific demethylase 1 inhibitor peptides and temporary cyclization to enhance proteolytic stability and cell growth-inhibitory activity." J. Med. Chem., 64, 3707-3719, 2021.
• Y. Amano, N. Umezawa, S. Sato, H. Watanabe, T. Umehara, T. Higuchi, "Activation of lysine-specific demethylase 1 inhibitor peptide by redox-controlled cleavage of a traceless linker."
Bioorg. Med. Chem., 25, 1227-1234, 2017.
• N. Umezawa, Y. Noro, K. Ukai, N. Kato, T. Higuchi, "Photocontrol of peptide function: Backbone cyclization strategy with photocleavable amino acid." ChemBioChem, 12, 1694-1698, 2011.

Peptides are flexible molecules that do not form stable conformations and therefore do not usually exhibit the strong activity of proteins. We are working to improve the activity of functional peptides by stabilizing their conformation. In addition to high activity, the molecules we are developing are expected to overcome the problem of low in vivo stability, which is one of the drawbacks of medium-sized molecules.
Recently, we are also developing a method to find peptides with high activity by using reversible covalent bond formation reactions. Stabilizing a functional conformation can produce peptides with strong activity, but it is difficult to predict which chemical modifications are appropriate, and it is necessary to synthesize and evaluate a large number of candidate compounds. We are working to develop new methods that can streamline this process.
 
References:
• Y. Imamura, N. Umezawa, S. Osawa, N. Shimada, T. Higo, S. Yokoshima, T. Fukuyama, T. Iwatsubo, N. Kato, T. Tomita, T. Higuchi, "Effect of helical conformation and side-chain structure on g-secretase inhibition by b-peptide foldamers: Insight into substrate recognition."
J. Med. Chem., 56, 1443-1454, 2013.
• Y. Imamura, N. Watanabe, N. Umezawa, T. Iwatsubo, N. Kato, T. Tomita, T. Higuchi, "Inhibition of g-secretase activity by helical b-peptide foldamers." J. Am. Chem. Soc., 131, 7353-7359, 2009.

We are interested in small organic molecules with polyamine (organic molecules with multiple amino groups) structures. It is known that polyamines such as spermine and spermidine exist in living organisms and are essential for cell proliferation. We have been developing solid-phase synthesis methods that enable efficient synthesis of polyamine derivatives, and are developing polyamine derivatives with various functions, such as those that function as enzyme inhibitors. In particular, we are developing polyamine derivatives that bind to nucleic acids and exhibit interesting functions, with the aim of applying them to nucleic acid-targeted pharmaceuticals.
 
References:
• N. Umezawa, K. Tsuji, S. Sato, M. Kikuchi, H. Watanabe, Y. Horai, M. Yamaguchi, Y. Hisamatsu, T. Umehara, T. Higuchi, "Inhibition of FAD-dependent lysine-specific demethylases by chiral polyamine analogues." RSC Adv., 8, 36895-36902, 2018.
• M. A. Gulshan, K. Tsuji, S. Matsumura, T. Higuchi, N. Umezawa, Y. Ikawa, "Distinct modulation of group I ribozyme activity among stereoisomers of a synthetic pentamine with structural constraints." Biochem. Biophys. Res. Commun., 504, 698-703, 2018.
• T. Nishio, Y. Yoshikawa, W. Fukuda, N. Umezawa, T. Higuchi, S. Fujiwara, T. Imanaka, K. Yoshikawa, "Branched-chain polyamine found in hyperthermophiles induces unique temperature-dependent structural changes in genome-size DNA." ChemPhysChem, 19, 1-7, 2018.
• A. Muramatsu, Y. Shimizu, Y. Yoshikawa, W. Fukuda, N. Umezawa, Y. Horai, T. Higuchi, S. Fujiwara, T. Imanaka, K. Yoshikawa, "Naturally occurring branched-chain polyamines induce a crosslinked meshwork structure in a giant DNA." J. Chem. Phys., 145, 235103, 2016.
• N. Umezawa, Y. Horai, Y. Imamura, M. Kawakubo, M. Nakahira, N. Kato, A. Muramatsu, Y. Yoshikawa, K. Yoshikawa, T. Higuchi, "Structurally diverse polyamines: Solid-phase synthesis and interaction with DNA." ChemBioChem, 16, 1811-1819, 2015.
• Y. Yoshikawa, N. Umezawa, Y. Imamura, T. Kanbe, N. Kato, K. Yoshikawa, T. Imanaka, T. Higuchi, "Effective chiral discrimination of tetravalent polyamines on single-DNA compaction. "
Angew. Chem. Int. Ed., 52, 3712-3716, 2013.

As tools to elucidate and regulate biological systems, we are interested in development of synthetic receptors that exhibit highly selective recognition for biomolecules. However, it is not easy to develop synthetic receptors that work in water, like proteins. We recently developed 4-aminoquinoline-based tweezer-type receptors for heme which plays various important roles in biological systems. Highly selective detection of heme using synthetic heme receptors in water is under progress.
 
References:
• Y. Hisamatsu, K. Otani, H. Takase, N. Umezawa, T. Higuchi, "Fluorescence response and self-assembly of a tweezer-type synthetic receptor triggered by complexation with heme and its catabolites", Chem. Eur. J., 2021, 27, 6489–6499.
• Y. Hisamatsu, N. Umezawa, H. Yagi, K. Kato, T. Higuchi, "Design and synthesis of a 4-aminoquinoline-based molecular tweezer that recognizes protoporphyrin IX and iron(III) protoporphyrin IX and its application as a supramolecular photosensitizer", Chem. Sci., 2018, 9, 7455-7467.

There are various beautiful self-assembly systems in nature. We are interested in development of unique self-assembly systems in water based on amphiphilic 4-aminoquinoline building blocks. For example, an amphiphilic 4-aminoquinoline-tetraphenylethene conjugate that exhibits stepwise self-assembly and has the ability of switching its kinetic nature in response to pH was developed.
 
References:
• Y. Hisamatsu, G. Toriyama, K. Yamamoto, H. Takase, T. Higuchi, N. Umezawa, "Temperature control of the self-assembly process of 4-aminoquinoline amphiphile: selective construction of perforated vesicles and nanofibers, and structural restoration capability", Chem. Eur. J., 2024. 30(36), e202400134.
• Y. Hisamatsu, F. Cheng, K. Yamamoto, H. Takase, N. Umezawa, T. Higuchi, "Control of the stepwise self-assembly process of a pH-responsive amphiphilic 4-aminoquinoline-tetraphenylethene conjugate", Nanoscale, 2023, 15, 3177-3187.