Innopodium- Kihara Laboratory

Our Mission

Our laboratory utilizes the latest drug discovery support technologies to create new agrochemicals, primarily fungicides, insecticides, herbicides, and plant growth regulators. By integrating both fundamental and applied research, we aim to discover novel active compounds that contribute to the agricultural sector.

We apply a multidisciplinary approach that includes:

By combining these specialized technologies, we can accelerate the development of innovative agrochemicals and contribute to the advancement of sustainable agriculture. Our research focuses on targets of agrochemical action sites and plant hormone receptors.

Research Highlights

The following is an example of our research achievements, where we not only discovered the world's first KAI2 inhibitor through a screening of our in-house library, but also designed and synthesized a compound with enhanced activity based on its binding mode with a protein. This work was published in the top journal, Nature Communications (http://www.nature.com/articles/s41467-024-54801-1).

In a collaborative study with a research group led by Associate Professor Takuya Miyakawa of the Kyoto University Graduate School of Biostudies, we developed KK181N1, the first compound to selectively inhibit KAI2, a receptor for karrikins (KARs), which are smoke-derived molecules produced during wildfires. We used structural biology to reveal its binding mode. This triazole urea-type compound binds to KAI2 non-covalently and can selectively suppress KAR-induced traits in the model plant Arabidopsis thaliana. Furthermore, KK181N1 was confirmed to specifically antagonize the KAR signaling pathway without affecting the strigolactone (SLs) signaling pathway, which is mediated by the D14 receptor, a protein with similar functions and compound receptivity to the KAR receptor. This discovery allows us to differentiate between the physiological functions of KARs and SLs, which have similar actions. Our research provides new insights into the fundamental study and agricultural applications of KARs.

Figure 1(a) shows the crystal structure of the complex of Arabidopsis thaliana KAI2 (AtKAI2) and KK181N1. Figure 1(b) the isothermal titration calorimetry (ITC) thermogram, confirming the binding of KK181N1 to AtKAI2. The binding is significantly influenced by the arrangement of hydrophobic residues within the pocket, which controls the orientation of the indole ring's methyl group, as well as by a hydrogen bond network mediated by a water molecule at the bottom of the pocket and surrounding residues. The formation of a catalytic triad (S95-H246-D217) was particularly crucial. These interactions allow KK181N1 to exhibit high affinity for KAI2 and act as a KAR antagonist. Based on this knowledge, we designed a more potent derivative, KKT3054, and demonstrated its powerful KAR-inhibiting activity (Figure 3).