Small molecular weight compounds such as proteostasis regulators have emerged as promising approaches to overcome some of these protein processing defects. The use of small molecule proteostasis modulators can enhance innate cellular proteostasis or proteostasis to fold mutant enzymes. CD BioSciences offers specialized proteostasis regulators drug discovery solutions for LSDs.
Background of Proteostasis Regulators for LSDs
Loss-of-function lysosomal storage diseases (LSDs) are often caused by extensive endoplasmic reticulum associated degradation of a mutated lysosomal enzyme instead of proper folding and trafficking. Different approaches have been used or proposed to treat LSDs, including enzyme replacement therapy and hematopoietic stem cell transplantation therapy, but these approaches have their own limitations. Missense mutations affecting enzyme stability, folding and cellular trafficking are common in LSDs and usually lead to low protein half-life, premature degradation, aggregation and retention of mutant proteins in the endoplasmic reticulum. To understand the molecular and cellular mechanisms behind LSDs, the concepts of protein homeostasis and lysosome dynamics need to be understood. Protein homeostasis is a combination of multiple integrated systems of regulation, including protein synthesis, structural folding, post-translational modifications, transport and degradation. These small molecule drugs, called proteostasis regulators, can modulate the capacity of this network and potentially restore the normal balance between protein folding, transport and degradation.
Fig. 1. Proteostasis regulators and pharmacological chaperones synergize to restore mutant enzyme homeostasis. (Mu TW, et al., 2008)
Solutions
Based on an extensive understanding of protein folding, proteostasis pathways and lysosomal biogenesis, our team of experts is developing several low molecular weight compounds to enhance protein folding and rescue some misfolded proteins from premature degradation. Here, CD BioSciences offers proteostasis regulators drug discovery solutions for LSDs to restore partially folded, transported and functionally misfolded lysosomal enzymes that are prone to endoplasmic reticulum (ER) associated degradation (ERAD) mutations. Intriguingly, our proteostasis regulators are low molecular weight compounds that promote protein folding and minimize misfolding by enhancing the expression and function of molecular chaperones and regulators of the endoplasmic reticulum quality control system.
Preclinical Development of Proteostasis Regulators
Signaling integration within the proteostasis network is associated with a wide range of gene regulation and leads to cell type-specific transcriptional patterns in response to stress to restore homeostasis in vivo. Working closely with proteologists, we are analyzing genes involved in proteostasis processes. We develop several promising compounds to ameliorate the effects or missense mutations caused by different LSDs. Proteostasis regulators are focused on the regulation of:
❖ Proteasome degradation pathways.
❖ Heat shock response (HSR).
❖ Calcium homeostasis.
❖ ERAD pathway.
❖ Lysosomal proteostasis.
Preclinical Development of Autophagy Regulators
We are working on the development of autophagy regulators to target autophagy-related pathways that can help reduce the accumulation of stores in LSDs by reactivating substrate degradation. The advantage of such molecules is that the same treatment can ideally be effective for different LSDs, independent of genetic defects.
Combined Use of Proteostasis Regulators and Pharmacological Chaperones
They have different mechanisms of action. We provide mouse models to analyze the effects of proteostasis regulators in combination with pharmacological chaperones on mutant enzyme function.
Properties of Proteostasis Regulators
- A proteostasis regulator molecule can be used to restore partial enzyme function in two different LSDs cell lines.
- Proteostasis regulators minimize misfolding/aggregation of mutant enzymes and improve folding efficiency.
- The combination of the "push" of the folded state by the proteostasis regulators and the "pull" of the original state by the pharmacological chaperones is much more effective than either one alone.
- Proteostasis regulators have an impact on the regulation of cellular gene expression in the degradation pathway.
We are very innovative in the development phase to achieve each client's individual goals. We are ready to explore the value of proteostasis regulators to meet the requirements of novel LSDs treatment strategies. For more information, please feel free to contact us.
Reference
- Mu TW, et al. (2008) Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell. 134(5): 769-81.