Adhesion molecule targeting

Adhesion molecule inhibitors Intracellular signalling targets (eg SMADs)... 

Jones, F. S., Prediger, E. A., Bittner, D. A., DeRobertis, E. M., and Edelman, G. M. (1992b). Cell adhesion molecules as targets for Hox genes neural cell adhesion molecule promoter activity is modulated by cotransfection with Hox-2.5 and -2.4. Proc. Natl. Acad. Sci. USA 89 2086-2090. 

Halichlorine 11 is a structurally unique alkaloid that was isolated from the sponge Halichondria okadai and found to act as an inhibitor of the induction of vascular cell adhesion molecule (VCAM-1), a potential target in the development of drugs for the treatment of several vascular diseases. The strategies employed for the construction of its spiroquinolizidine unit are summarized in Scheme 106. 

Cell adhesion molecules (CAMs) play critical roles in all facets of nervous system development and maintenance. Important phenomena in which CAMs are involved include initial formation of the neural tube and the neural crest, migration of all neurons and glial cells, axonal outgrowth and guidance, target selection, synaptic stabilization and plasticity, myelination and nerve regeneration after injury (see Chs 4,24,28-30 and 53). Adhesion molecules interact with each other and with nonadhesive cell-surface and/or cytoplasmic molecules, and, in the two... 

Mercier, G. T., Campbell, J. A., Chappell, J. D., Stehle, T., Dermody, T. S., and Barry, M. A. (2004). A chimeric adenovirus vector encoding reovirus attachment protein sigmal targets cells expressing junctional adhesion molecule 1. Proc. Natl. Acad. Sci. USA 101, 6188-6193. 

The final chapter, by Hounsell (London), also relates to an important aspect of glycoprotein structure, namely the structures and shapes, as determined by physicochemical methods, of oligosaccharide determinants of glycoproteins that are antigens and targets for binding of adhesion molecules. 

In most, if not all, chronic inflammatory diseases endothelial cells are prominently involved in the disease process. This is demonstrated by an increased expression of adhesion molecules and production of cytokines, and their pro-angiogenic behaviour. This leads to continuous recruitment of leucocytes into the inflamed area, without (detectable) antigen present in the affected tissue, resulting in a vicious circle of tissue damage and leucocyte recruitment. Targeting inhibitory agents (in)to the endothelial cell may interrupt in this process by controlling the activation status of this cell type. 

A selective method of preventing the expression of adhesion molecules or cytokines is the use of antisense oligonucleotides. These oligonucleotides are short sequences of nucleic acids complementary to mRNA sequences of specific proteins of interest. If delivered to the cytoplasmic compartment of cells these oligonucleotides are able to form a complex with their target mRNA. In this way the translation of mRNA into protein by ribosomes is inhibited. The subsequent mRNA degradation by RNAse H results in reduced expression of the protein (see also Chapter 5 for a description of antisense ohgonucleotides as therapeutic modalities). 

As stated earlier, activation of endothelial cells by pro-inflammatory stimuli leads to the expression of cell adhesion molecules and cytokines such as IL-6 and IL-8. The expression and hence modulation of surface expressed adhesion molecules by e.g. targeted delivery of inhibitors of NFkB, can be measured using flow cytometric analysis or whole cell ELISA techniques. Cytokine production can be measured in the supernatant of cultured cells or in biological fluids. Furthermore, competitive or quantitative RT-PCR analysis of mRNA levels of cell adhesion molecules or cytokines, allows the transcriptional activity of the genes of interest to be estimated. 

Bearing these considerations in mind, of the presently identified endothelial adhesion molecules, E-selectin in particular seems to be a suitable epitope for targeting chronic inflammatory endothelial cells. 

Selected adhesion molecules represent yet another antibody target. Adhesion molecules, such as LFA-1 (leukocyte function-associated antigen-1) and ICAM-1 (intercellular adhesion molecule 1), play central roles in promoting migration of inflammatory cells to the sites of damage. Such activities underlie many of the symptoms of conditions such as rheumatoid arthritis. Inhibition of adhesion molecule function by administration of antibodies raised against them may, therefore, demonstrate therapeutic potential in some instances. 

TNF-a and IL-1 are current targets of antiinflammatory drug therapy. A homotrimer of 17-kDa protein subunits whose effects include the activation of neutrophils and eosinophils, induction of COX-2, induction of proinflammatory cytokines (e.g., IL-1, IL-6), enhancement of endothelial layer permeabihty, induction of adhesion molecules by endothelial cells and leukocytes, stimulation of fibroblast proliferation, degradation of cartilage, and stimulation of bone reabsorption. Two receptors mediate these effects a 55-kDa receptor (p55) and a 75-kDa receptor (p75). Each of these receptors is found in both cell surface and soluble forms. The binding of two or three cell surface receptors to TNF-a initiates an inflammatory response. Soluble p55 also acts as a signaling receptor for inflammatory responses, whereas soluble p75 acts as an antagonist. 

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