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Discovery of allosteric regulators with clinical potential to stabilize alpha-L-iduronidase in mucopolysaccharidosis type I

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Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disease (LSD) that arises from mutations in the gene encoding the lysosomal hydrolase alpha-L-iduronidase (IDUA) protein. This deficiency prevents the breakdown of glycosaminoglycans (GAGs), such as heparan and dermatan sulfates, leading to their accumulation in various organs. This buildup triggers a series of intracellular events that cause tissue damage, organ dysfunction, and, in severe cases, early death.


Clinical Manifestations and Current Treatments

MPS I presents a spectrum of clinical phenotypes. The most severe form is Hurler syndrome, while the milder forms include Scheie and Hurler-Scheie syndromes. Hurler-Scheie syndrome represents an intermediate phenotype, making up about 23% of MPS I cases.

Treatment approaches vary based on the severity of the disease. For patients with attenuated MPS I, enzyme replacement therapy (ERT) is the primary treatment. This involves weekly intravenous infusions of recombinant human IDUA (rhIDUA), known as laronidase (Aldurazyme). However, the short plasma half-life of rhIDUA (1.5 to 3.6 hours) and its immunogenicity limit its effectiveness. ERT can improve several systemic aspects of MPS I, such as organomegaly and glycosaminoglycanuria, but it has limited impact on skeletal and cognitive symptoms due to poor penetration in tissues with limited blood circulation and barriers like the blood-brain barrier.

For the most severe MPS I cases, hematopoietic stem cell transplant (HSCT) is recommended, ideally before the patient is 2.5 years old. HSCT can provide long-term benefits, but it carries significant risks and is not suitable for all patients.


Advancements in Treatment: Pharmacological Chaperone Therapy

Recent advancements explore combining ERT with pharmacological chaperone therapy (PCT). PCT uses small molecules to stabilize lysosomal enzymes, enhancing their activity and distribution. This combined approach has shown promise in other lysosomal storage disorders like Fabry and Gaucher diseases. A combination of ERT and PCT could improve enzyme stability and reduce immunogenicity, enhancing overall treatment efficacy.


Site-directed Enzyme Enhancement Therapy (SEE-Tx1)

A novel approach involves the SEE-Tx1 platform, a computational drug discovery method that identifies new allosteric binding sites and drug-like molecules. This method has been used to discover pharmacological chaperones, known as structure-targeted allosteric regulators (STARs), for IDUA.


Research and Development Using SEE-Tx1

The SEE-Tx1 platform identified a new allosteric binding site in IDUA, leading to the virtual screening of millions of compounds. This resulted in the discovery of a promising small molecule, GT-01803, which demonstrated positive effects on IDUA activity and good oral bioavailability.


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Experimental Validation and Results

  • Virtual Screening and Hit Identification: The SEE-Tx1 platform screened over 4.8 million compounds, narrowing it down to 78,045 potential hits. Further computational and medicinal chemistry analysis identified 185 compounds for experimental validation. Differential scanning fluorimetry (DSF) confirmed 21 compounds as effective stabilizers of IDUA.
  • GT-01803 Stability and Activity: GT-01803 showed significant thermal stabilization of IDUA in vitro, improving enzyme stability at physiological conditions. In patient-derived fibroblasts, GT-01803 enhanced IDUA activity, suggesting a potential for improved therapeutic outcomes.
  • Pharmacokinetics and Biodistribution in Mice: In vivo studies in mice showed that GT-01803 is orally bioavailable and significantly enhances the biodistribution and activity of IDUA when co-administered with rhIDUA. This indicates a promising future for combination therapies involving ERT and STARs.


Conclusion and Future Directions

The discovery of GT-01803 through the SEE-Tx1 platform represents a significant step forward in the treatment of MPS I. This novel approach could enhance the efficacy of existing ERT, reduce associated adverse effects, and lower treatment costs. Further research and clinical trials are needed to validate these findings and potentially bring new, more effective treatments to patients with MPS I.

By leveraging advanced computational methods and innovative therapeutic strategies, the future holds promise for significantly improving the quality of life for individuals affected by this rare genetic disorder.

Note: SEE-Tx is the predecessor to Magellan. Magellan combines quantum physics and artificial intelligence to identify novel binding sites and small molecule drugs by employing sophisticated molecular modeling and quantum-driven simulations. Utilizing proprietary algorithms and powerful computing resources, Magellan maps protein surfaces, identifies druggable pockets, and searches an expansive virtual chemical space to design custom small molecule drugs for therapeutic targets.


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