Endogenous Lectins as Drug Targets

Abstract

The lysosome is an intracytoplasmic acidic vacuole containing more than 60 hydrolytic enzymes for digestion of macromolecules, such as nucleic acids, proteins, lipids and complex carbohydrates. Expression of lysosomal enzyme activities is regulated by various intracellular environmental factors. Mutation of a gene coding for a lysosomal enzyme results in a specific genetic disease, often involving the central nervous system in children. Three groups of functional proteins are known at present for regulation of the expressed enzyme activity in lysosomes. Targeting of a newly synthesized protein is achieved by the mannose 6-phosphate receptor system, which was revealed in the course of I-cell disease research. Many lysosomal enzymes are excessively secreted in the extracellular compartment in the absence of this regulatory system in patients with this disease (Kornfeld and Sly 2001). Lysosomal enzymes are also components of cell type-specific compartments referred to as lysosome-related organelles which include melanosomes, lytic granules, MHC class II compartments, platelet-dense granules, and synaptic-like microvesicles. Lysosomal storage diseases (LSDs) are inherited metabolic disorders caused by deficient activity of a single lysosomal enzyme or other defects resulting in deficient catabolism of large substrates in lysosomes. There are more than 40 forms of inherited LSDs known to occur in humans, with an aggregate incidence estimated at 1 in 7,000 live births. Clinical signs result from the inability of lysosomes to degrade large substrates; because most lysosomal enzymes are ubiquitously expressed, a deficiency in a single enzyme can affect multiple organ systems. Thus LSDs are associated with high morbidity and mortality and represent a significant burden on patients and society. Because lysosomal enzymes are trafficked by M6PR mechanism, normal enzyme provided to deficient cells can be localized to the lysosome to reduce and prevent storage. However, many LSDs remain untreatable, and gene therapy holds the promise for effective therapy. Other therapies for some LSDs do exist, or are under evaluation, including heterologous bone marrow or cord blood transplantation (BMT), enzyme replacement therapy (ERT), and substrate reduction therapy (SRT), but these treatments are associated with significant concerns, including high morbidity and mortality (BMT), limited positive outcomes (BMT), incomplete response to therapy (BMT, ERT, and SRT), life-long therapy (ERT, SRT), and cost (BMT, ERT, SRT). Moreover, proteins, vesicles, nano-particles or other polymers could be functionalized with mannose 6-phosphate or its analogues in order to be used as carriers of bioactive molecules for the treatments of different diseases (Gary-Bobo et al. 2007).