Intracellular degradation

One of the limitations of the use of a proteinaceous carrier is the relative small number of drug molecules that can be conjugated without gross alterations in the structure of the protein. For example, extensive derivatization of an antibody carrier may lead to the loss of its 

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Ribozymes are small RNA molecules with endoribo-nuclease activity. Under appropriate conditions, ribozymes exhibit sequence-specific cleavage of the target. The cleaved mRNA is destabilized and subject to intracellular degradation. 

Niacin (vitamin B3) has broad applications in the treatment of lipid disorders when used at higher doses than those used as a nutritional supplement. Niacin inhibits fatty acid release from adipose tissue and inhibits fatty acid and triglyceride production in liver cells. This results in an increased intracellular degradation of apolipoprotein B, and in turn, a reduction in the number of VLDL particles secreted (Fig. 9-4). The lower VLDL levels and the lower triglyceride content in these particles leads to an overall reduction in LDL cholesterol as well as a decrease in the number of small, dense LDL particles. Niacin also reduces the uptake of HDL-apolipoprotein A1 particles and increases uptake of cholesterol esters by the liver, thus improving the efficiency of reverse cholesterol transport between HDL particles and vascular tissue (Fig. 9-4). Niacin is indicated for patients with elevated triglycerides, low HDL cholesterol, and elevated LDL cholesterol.3... 

The mechanism of the intracellular degradation of poly(HA) by bacteria, i.e., the mobilization of a previously accumulated polyester, is poorly understood (see also the chapter by Babel et al. in this book). Most of the research on intracellular poly(3HB) mobilization was done more than 30 years ago. Lemoigne observed in 1925 that 3-hydroxybutyrate was the main product of anaerobic breakdown of poly(3HB) in Bacillus M [12,137]. Macrae and Wilkinson [138, 139] noticed a reduction of the poly(3HB) content of Bacillus megaterium upon aerobic incubation of poly(3HB)-rich cells in phosphate buffer. The authors found that autolysis of poly(3HB)-rich cells occurred later and to a minor extent compared to poly(3HB)-poor cells and proposed that poly(3HB) might... 

WRF presents an intracellular enzymatic system, cytochrome P450 monooxigenases, similar to those mammalian cells, that catalyzes a broad range of intracellular degradation reactions of released metabolites after the pollutants breaking by extracellular enzymes. 

Akagi T, Shima F, Akashi M (2011) Intracellular degradation and distribution of protein-encapsulated amphiphilic poly(amino acid) nanoparticles. Biomaterials 32 4959 1967... 

Proteasome inhibition by lactacystin and Bz-LLL-COCHO (benzol-Leu-Leu-Leu-glyoxal) causes a significant increase of ABP and cell death by altering APP processing at the y-secretase site (406). Resveratrol does not inhibit ABP production because it has no effect on 3-, or y-secretases, but promotes instead intracellular degradation of ABP via a mechanism that involves the proteasome. The resveratrol-induced decrease of ABP can be effectively prevented by several selective proteasome inhibitors and by small interfering RNA-directed silencing on the proteasome subunit P5 (407). 

Formation of antigens from the intracellular degradation of pathogens The proteolytic system hydrolyses proteins of pathogens that are present within the host cell (e.g. a virus), to produce a short peptide which forms a complex with a specific protein, known as the major histocompatibility complex (MHC) protein. The peptide is, in fact, the antigen. At the plasma membrane, the MHC protein locates within the membrane and the small peptide sits on the outside of the membrane, where it can interact with the receptor on a cytotoxic T-lymphocyte to kill the host cell and the virus (Chapter 17). 

Tellam J, Sherritt M, Thomson S, Tellam R, Moss DJ, Burrows SR, Wiertz E, and Khanna R (2001) Targeting of EBNAl for rapid intracellular degradation overrides the inhibitory effects of the Gly-Ala repeat domain and restores CD8+ T cell recognition. J. Biol. Chem. 276 33353-33360. 

Ahrenholtz, 1., Lorenz, M. G. Wackernagel, W. (1994). A conditional suicide system in Escherichia coli based on the intracellular degradation of DNA. Applied and Environmental Microbiology, 60, 3746-51. 

Chloroquine drastically improves the transfection of cells when DNA/polylysine conjugates are used (Zenke et al., 1990 Midoux et al., 1993). So far, the mechanism of action of chloroquine has not been completely elucidated. Chloroquine is supposed to protect the internalized plasmid from intracellular degradation as a result of the neutralization of acidic compartments and the inhibition of endosome fusion with lysosomes. Furthermore, the swelling of vesicles can be induced when the concentration of chloroquine is high enough. However, there is no direct relationship between the neutralization of the acidic cell compartments and the transfection efficiency (Erbacher et al., 1996a). Once taken up by the cells, chloroquine accumulates inside acidic vesicles where it can reach a concentration more than 50 mM, based on the estimated volume of the vesicular compartments. At physiological pH, 82% of chloroquine is protonated and can bind to nucleic acids. Therefore, the interaction of chloroquine with DNA appears to be... 

Different hypotheses have been raised to explain these purported beneficial effects. Ono et al. have shown that the neuroprotective effects of various polyphenols (e.g., myricetin, morin, and, to a lesser extent, quercetin) may be due to their ability to inhibit amyloid fibrils and to destabilize fibrilized forms of Ap,20 suggesting that they could be considered as new therapeutic agents for the treatment of AP-associated diseases.21 Resveratrol, a red-wine polyphenol, has been proposed to promote the intracellular degradation of Ap by a proteasome-dependent and secretase-independent activity.22 Based on these findings, we compared the effects of polyphenols found in teas and red wine, using the model of AP-induced toxicity in rat hippocampal primary cell cultures. 

At least to some extent they can provide protection for nucleic acids toward both extracellular and intracellular degradation during the long journey to the cell nucleus (El Ouahabi, Thiry et al. 1997) as illustrated in Fig. 12.2. 

Intracellular degradation is most specific against di-peptides and occurs mainly in lysosomes, but also in other intracellular organelles. 

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