Background of Drug Discovery Targeting Lysosomal Acidification
The acidic environment of lysosomes is not only a structural feature, but also the basis for their activity and function. The basic lysosomal pH is 4.5-5.0 with a buffering capacity of 19±6 mM/pH unit and multiple channels. Dysregulated lysosomal acidification leads to impaired endocytosis, autophagic degradation, macromolecular biogenesis and transport and is observed in protein-based neurodegenerative diseases, metabolic disorders and immune diseases. Lysosomal acidification dysfunction also affects the activity of other organelles, leading to increased production of reactive oxygen species and inflammatory cytokines, which contribute to the pathogenesis of inflammatory diseases, cancer and infectious diseases. Therefore, lysosomal pH is an attractive and targetable site for therapeutic intervention.
Fig. 1. v-ATPase defects and associated neurodegenerative diseases. (Colacurcio D J, et al., 2016)
Solutions
Lysosomal acidification plays different roles in different diseases, our scientists can select the appropriate targeting measures depending on the lysosomal acidification status. Our goal is to help you design drugs that specifically regulate lysosomal pH and rescue associated cellular functional impairment by synthesizing new materials or reagents that regulate lysosomal pH. At CD BioSciences, we are committed to providing our global customers with targeting strategies for lysosomal acidification in human diseases. We provide biomaterial design strategies for modulating lysosomal pH.
Ensuring Effective Lysosome Targeting
Specific lysosomal targeting is important, as non-specific organelle targeting can crosstalk and modulate lysosomal function. We target materials (molecular or nano-sized) to lysosomes through two main strategies.
- By incorporating lysosomal membrane targeting motifs, such as tyrosine-based (Y) motifs with YXXφ shared sequences, DXXLL patterns of double leucine-based motifs, morpholino chemical groups.
- Using nanoparticles with diameters ranging from 25-200 nm, these particles rapidly enter the cell and localize to the lysosome via endocytosis. We fine-tune the size and shape of the nanoparticles by varying the material, synthesis method and type of surface ligand to improve their targeting and localization efficiency.
Stimulus-Responsive Biodegradable Junctions
We use polymers with weakly acidic or basic residues (polyesters, polyanhydrides, polycarbonates, etc.) as lysosomal pH-responsive polymers to raise or lower lysosomal pH in disease. They enable higher tissue penetration depth, degradation in the lysosomal environment, and can be used in in vivo models.
Released alkaline/acidic functional groups increase/decrease lysosomal pH
We increase lysosomal pH by adding the presence of alkaline side chain small molecules (such as hydroxychloroquine (HCQ) and chloroquine (CQ)) to the disease model. Inaddition, we decreased lysosomal pH by adding polyesters, poly(lactic-co-glycolic acid) (PLGA) to the disease model.
Why Choose Us
- A variety of material designs and strategies to ensure effective lysosomal targeting and modulation of lysosomal pH.
- Appropriate targeting measures can be selected for different lysosomal acidification states.
- Design of properly controlled experiments to ensure that changes in cellular function are solely due to changes in lysosomal pH.
- Collaborate with experienced international technical staff.
CD BioSciences can meet any reasonable needs of our clients, taking time and budget into consideration for you. Our aim is to be customer-centric and to provide the highest quality services to customers. Our customer service representatives are enthusiastic and trustworthy 24 hours a day, 7 days a week. If you are interested in our services, please feel free to contact us for more information or a detailed discussion.
Reference
- Colacurcio D J, Nixon R A. (2016) Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease[J]. Ageing research reviews. 32: 75-88.