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The Next Chapter of Precision Chemical Modification: From Natural Product Inspirations to Efficient Drugs for Rare Disease

The last day of February each year marks International Rare Disease Day, falling on February 29th every four years, coincidentally echoing the unique significance of rare diseases. This initiative was first launched by the European Organisation for Rare Diseases (EURORDIS) on February 29, 2008. Each year, the organization shares stories of rare disease families globally through various themes, aiming to raise awareness and compassion for rare diseases among the general public and to encourage the development of treatments for rare diseases.

"Natural is Still the Best!" Scientists have isolated numerous small molecules with potential biological activity from natural sources. However, these molecules often require chemical modifications and structural refinements to unleash their full potential. Design and synthesis of "more precise" and "more effective" molecules to enhance their efficacy and reduce their side effects became the most challenging tasks in natural drug development.

Dr. Wei-Chieh Cheng’s lab has been devoted to the chemical synthesis, structural modification, and biological activity exploration of natural alkaloids at the Genomics Research Center of Academia Sinica. In recent years, they have extended their research efforts to enhance the efficacy of protein drugs for rare diseases. Through precise chemical modification strategies and molecular structure optimization, they discovered a novel pharmacological chaperone that significantly enhances the efficacy of protein drugs for treating Fabry disease, a rare genetic disorder. This research breakthrough was published earlier this year in JACS Au, paving new avenues for precise molecular design.

In Taiwan, the two most common rare diseases are multiple sclerosis (MS)/neuromyelitis optica spectrum disorder (NMOSD) due to severe immune reactions and amyotrophic lateral sclerosis (ALS) caused by protein misfolding and nerve degeneration. In recent years, there has been a rising number of reported cases of lysosomal storage diseases (LSDs), especially Fabry disease (FD). FD arises from mutations in the GLA gene, causing misfolded α-galactosidase to be degraded in the endoplasmic reticulum instead of being transported to lysosomes. The accumulation of specific metabolites (globotriaosylceramide, Gb3) leads to various complications, ranging from skin lesions characterized by purplish-black discoloration to intermittent pain or abnormal sensations in the hands and feet, significantly impacting quality of life. Dr. Dau-Ming Niu's lab at Taipei Veterans General Hospital's Department of Pediatrics has discovered that the prevalence of Fabry disease among Taiwanese is much higher than the previous estimation, highlighting the importance of improving current treatment strategies.

Clinically, utilizing small molecules (pharmacological chaperones) to stabilize α-galactosidase has been a current therapeutic strategy for treating Fabry disease. These molecules can selectively bind to specific lysosomal enzymes, not only preventing enzyme degradation in the endoplasmic reticulum but also protecting the stability of enzyme drugs in the circulatory system. The protecting effect of molecules improves the transportation of enzymes to lysosomes hydrolyzing metabolic substrates. However, existing pharmacological chaperones mostly fail to effectively dissociate from the enzymes in lysosomes, thereby affecting the efficiency of substrate degradation. Dr. Cheng's lab has successfully developed a novel pharmacological chaperone possessing superior pH-selectivity through innovative precise chemical synthetic strategies. The synthesized molecules can effectively dissociate from enzymes in lysosomes, thereby enhancing the hydrolytic efficacy of enzymes and reducing side effects (Figure 1).

2024ACK170 F1
Figure 1. Pharmacological chaperone for the treatment of lysosomal storage disease

 

In 2016, Dr. Wei-Chieh Cheng's laboratory employed a natural product-inspired combinatorial chemistry (NPICC) strategy to develop a series of pyrrolidine-based iminosugars. Through collaboration with Dr. Dau-Ming Niu at Taipei Veterans General Hospital, they successfully developed a patent molecule, ACK170 (PCT/US2017/037381), from the molecular library, possessing chaperone activity toward the enzyme drug (α-Gal A) for Fabry disease. The research provides a comprehensive explanation of how pyrrolidine-based polyhydroxylated alkaloids interact with glycosidase at the molecular and atomic levels, and reveals that both exocyclic and endocyclic amino groups contribute to the pH-selective binding and protecting effect on the enzyme.

The first author of this article, Dr. Huang-Yi Li remarked, "The exocyclic amino group on iminosugar is quite different! Leveraging this difference can enhance the binding affinity of the molecule to glycosidase, and the effect is very significant."

In the crystallographic studies, as well as thermodynamic and kinetic studies, researchers found that the strong binding affinity between ACK170 and α-Gal A in neutral pH environments stems from the electrostatic interactions between the exocyclic amino group of ACK170 and the carboxyl groups of α-Gal A (D231 and E203). In contrast, these interactions become weaker in acidic pH environments due to the protonation of the carboxyl groups (Figure 2). These results demonstrate that introducing an additional amino group onto the iminosugars can enhance the binding affinity and pH-selectivity of small molecules to the enzyme, paving the way for the development of next-generation pharmacological chaperones in the future.

2024ACK170 F2
Figure 2. The interactions between ACK170and α-Gal A in different pH environments.

 

Furthermore, the researchers from the Department of Pediatrics at Taipei Veterans General Hospital conducted in vivo experiments to evaluate the therapeutic potential of ACK170 by using Fabry mice models. The results suggested that ACK170 significantly increased the half-life of α-Gal A in the circulatory system after co-administration of the α-Gal A and ACK170, as well as the enzymatic activity and enzyme levels in the heart, liver, and kidneys. These results confirm that ACK170 can enhance tissue uptake of α-Gal A by prolonging absorption time by tissues in the circulatory system, promoting tissue uptake in vivo (Figure 3).

2024ACK170 F3
Figure 3. ACK170 can stabilize α-Gal A in the circulatory system and improve tissue uptake in Gla KO mice.

 

Due to the low prevalence and relatively small populations, there is a lack of sufficient diagnosis, treatment, and drug development studies for rare diseases. "Enhancing the selectivity of drugs can reduce their side effects," Dr. Wei-Chieh Cheng emphasizes, "Understanding the binding modes and interactions at the molecular and atomic levels, combined with precise chemical modification strategies, our finding will help synthesize and design novel pharmacological chaperones for other rare diseases."

This study was a collaborative effort involving teams from the Genomics Research Center at Academia Sinica and Taipei Veterans General Hospital. Key contributors include Professor Wei-Chieg Cheng and Dr. Huang-Yi Li, along with Director Dau-Ming Niu and Dr. Sheng-Kai Chang from the Department of Pediatrics, as well as Senior Research Specialist Kai-Fa Huang from the Institute of Biological Chemistry. The full paper, titled "Mechanistic Insights into Dibasic Iminosugars as pH-Selective Pharmacological Chaperones to Stabilize Human α-Galactosidase" is available for online reading at: https://pubs.acs.org/doi/10.1021/jacsau.3c00684

 

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