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2024-04-26
  • Research Findings
  • Institute of Molecular Biology
Unraveling how a predatory fungus sense its nematode prey

The capability to sense and respond to the environment is essential for survival and fitness in all organisms. Recent studies have shown organisms from different kingdoms, such as fungi, plants, and mammals can recognize and respond to conserved nematode pheromones, named ascarosides. However, the mechanisms underlying cross kingdom perception of nematode pheromones remain unclear. A research team led by Dr. Yen-Ping Hsueh at the Institute of Molecular Biology, Academia Sinica, revealed that two families of GPCRs are responsible for ascarosides detection, leading to the activation of the cAMP-PKA pathway for trap development in nematode-trapping fungus Arthrobotrys oligospora. The expansion of GPCRs in A. oligospora may have been advantageous for recognizing diverse nematode-derived signals to ensure robust prey recognition during co-evolution. Moreover, the identification of ascarosides receptors in a fungal species sheds light on the molecular mechanisms of ascaroside-mediated cross-kingdom communication. This research has been published on April 22, 2024 in Nature Microbiology. The lead author of this research, Chih-Yen Kuo, is a TIGP-MCB student at Academia Sinica, and collaborators of this research includes Dr. Frank Schroeder at Cornell University and Dr. Yu-Chu Chang at Taipei Medical University. Funding was provided by Academia Sinica and the National Science and Technology Council.

2024-03-28
  • Research Findings
  • Genomics Research Center
The Next Chapter of Precision Chemical Modification: From Natural Product Inspirations to Efficient Drugs for Rare Disease

The use of protein stabilizers or pharmacological chaperones to protect specific enzymes and impart a therapeutic benefit is an emerging strategy in drug discovery. However, designing molecules that can bind optimally to their targets at physiological pH remains a major challenge. The research, led by Dr. Wei-Chieh Cheng at Genomics Research Center, Academia Sinica, found that a dibasic polyhydroxylated pyrrolidine ACK170 (US 10995067 B2) exhibited superior pH-selective inhibitory activity and chaperoning activity for human α-galactosidase A (α-Gal A) through the Natural Product-Inspired Combinatorial Chemistry (NPICC) strategy. To further investigate the role of different C-1 moieties on the pH-selectivity and protecting effects of these compounds, researchers designed and synthesized a library of monobasic and dibasic iminosugars, screened them for α-Gal A stabilizing activity using thermal shift and heat-induced denaturation assays, and characterized the mechanistic basis for this stabilization using X-ray crystallography and binding assays. It was noted that the dibasic iminosugar ACK170 protect α-Gal A from denaturation and inactivation at lower concentrations than monobasic or other N-substituted derivatives; a finding attributed to the nitrogen on the C-1 methylene of ACK170 which forms the bifurcated salt bridges with two carboxyl residues, E203 and D231, and is responsible for their pH-selective binding to α-Gal A. Moreover, ACK170 demonstrated promising results to improve enzyme replacement therapy and exhibited significant chaperoning effects in Fabry cells. These findings suggest that amino-iminosugar ACK170 is a useful model to demonstrate how an additional exocyclic amino group can improve their pH-selectivity and protecting effects. This research has been published on February 23, 2024 in JACS Au, providing new insights into the design of pH-selective small molecules for the treatment of lysosomal storage diseases.

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