Pharmacological chaperone therapy(PCT) is an emerging approach for the treatment of lysosomal storage diseases (LSDs). Small molecule chaperones interact with mutant enzymes, facilitating their proper conformation and enhancing their stability. CD BioSciences offers specialized pharmacological chaperones therapeutic drug discovery solutions for LSDs.
Background of Pharmacological Chaperones Therapy for LSDs
The balance between protein synthesis, folding and degradation is a closely monitored and highly dynamic process that is critical for maintaining cellular protein homeostasis. Misfolded or mutated proteins are degraded by the proteasome. In the case of many LSDs, missense mutations cause abnormal folding of lysosomal enzymes, thus preventing them from reaching the lysosome and performing their functions. Specific molecules called "chaperones" (e.g., Bip, heat shock proteins and calcium-linked proteins) usually help the protein to fold into the proper conformation. Therefore, scientists have proposed several small molecule approaches to correct the defects caused by mutations in lysosomal enzymes so that these mutant enzymes can acquire the correct conformation and possibly restore at least some of their catalytic activity. A more promising and advanced approach is the use of PCT to treat LSDs, which can selectively bind and stabilize mutant enzymes, increase their cellular levels, and improve lysosomal transport and activity.
Fig. 1. Mechanism of action of pharmacological chaperones. (Parenti G, et al., 2015)
Solutions
Protein misfolding as a disease mechanism (protein misfolding diseases) has attracted a lot of attention due to its obvious implications for human treatment. Our team of experts has designed and explored different approaches to rescue mutant proteins. Based on our years of experience studying small molecules in LSDs, CD BioSciences developes pharmacological chaperones therapy as an emerging approach based on small molecule ligands.
Interestingly, our pharmacological chaperones are low molecular weight chemical molecules that act by specifically binding to their target proteins and should not be confused with protein molecular chaperones. CD BioSciences offers customized PCT drug discovery solutions for LSDs.
Preclinical Development of Pharmacological Chaperones
Most of the pharmacological chaperones we develop are found in reversible competitive inhibitors. In addition, we work closely with biologists to find metastable ligands that stabilize missense-unstable mutants but do not bind the active site and do not inhibit activity, including the use of computer docking to identify metastable binding sites on the surface of enzymes and to find ligands in different chemical fragments.
We design chaperones to interact with mutant enzymes in the endoplasmic reticulum (ER), facilitating their correct conformation and enhancing their stability and translocation to the lysosome. In addition, we work on the identification of new chaperones, including new mutagenic drugs, and on the development of synergies between chaperone therapy and other therapeutic approaches.
Determination of the Stabilizing Effect of Pharmacological Chaperones
We offer a variety of methods to determine the stability of pharmacological chaperone：
❖ Chemical-physical techniques: differential scanning calorimetry, circular dichroism.
❖ Thermal transfer assay technique: this method allows the simultaneous processing of many samples, and requires a small amount of protein and equipment that is available in most biomedical laboratories. It is usually used to screen relatively large librarie.
❖ The stabilizing effect of chaperones is tested in vitro on mutant proteins present in cell extracts.
Binding of Chaperones to ERTs
We incubate pharmacological chaperones with wild-type recombinant enzymes of enzyme replacement therapy (ERT) to significantly increase the stability and potency of the recombinant enzymes.
Advantages of Our Solutions
- Chaperone proteins are small molecules that diffuse across the cell membrane and reach therapeutic concentrations in specific cellular septa.
- Chaperone proteins are the active sites for many ligand-binding enzymes.
- Pharmacological chaperones can cross the blood-brain barrier.
- Chaperone proteins are not immunogenic.
- PCT can be administered orally.
- PCT has a broad biodistribution and a positive impact on the quality of life of patients.
- PTC is effective either as monotherapy or in combination with ERT.
We are very innovative in the development phase to achieve each client's individual goals. We are ready to explore the value of PCT to meet the requirements of novel LSDs treatment strategies. For more information, please feel free to contact us.
Reference
- Parenti G, Andria G, Valenzano KJ. (2015) Pharmacological Chaperone Therapy: Preclinical Development, Clinical Translation, and Prospects for the Treatment of Lysosomal Storage Disorders. Mol Ther. 23(7):1138-1148.