Biomedical Engineering Reference
In-Depth Information
was found that the binding of FK506 to FKBP inhibits immune function by shutting down a specii c
molecular signaling pathway. Another natural product, galanthamine (Figure 4.4, see Chapter 16),
which is an inhibitor of acetylcholinesterase (AChE) isolated from certain species of daffodil and
is used for the treatment of mild to moderate Alzheimer's disease, was used as a template for the
so-called biomimetic DOS; that is, a range of diverse chemical reactions was applied to a scaffold
similar to that of galanthamine. A 2527 compound library of galanthamine-like structures was pre-
pared and underwent phenotypic screening, identifying secramine (Figure 4.4), as an inhibitor of
vesicular trafi c out of the Golgi apparatus by an unknown mechanism. After an extensive effort it
was discovered that secramine inhibits the activation of the Rho GTPase Cdc42, a protein involved
in membrane trafi c.
4.2.2.2 ChemBank and PubChem
Along the systematization of the application of small molecules to probe protein function, it follows that
the results of screening are put into a well-structured format, that is, a format where chemical structures
and biological activities are correlated. Two initiatives, ChemBank and PubChem, in this direction have
been initiated, which have very similar objectives, to create a public, Web-based informatics environ-
ment, with data derived from small molecules and small-molecule screens. The intention of such
databases is to guide the chemist in their synthesis of novel compounds or libraries, and assist biologists,
who are exploring small molecules that perturb certain biological pathways. These databases contain an
increasingly varied set of cell measurements derived from biological objects and cell lines treated with
small molecules. Moreover, analysis tools are available and are being developed that allow the relation-
ships between cell states, cell measurements, and small molecules to be determined.
4.3 MODIFYING BIOMACROMOLECULES
Biomacromolecules are oligomeric molecules that are composed of smaller building blocks in
nature. The three major classes of biomacromolecules are proteins, nucleic acids, and polysaccha-
rides, built up of amino acids, nucleotides, and carbohydrates, respectively.
The modii cation of nucleic acids is a very promising and fruitful area of research, where peptide
nucleic acid (PNA) and locked nucleic acid (LNA) are prominent examples of modii ed nucleic acids
(Figure 4.5). In PNA, the deoxyribose of the DNA backbone is replaced with N -(2-aminoethyl)-
glycine units. This has several advantages, for example, the backbone is linked by peptide bonds,
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FIGURE 4.5 Examples of two very successful modii ed structures of DNA/RNA: PNA, where the deoxyribose
of the DNA backbone is replaced with N -(2-aminoethyl)-glycine units, and LNA, where the ribose moiety is
modii ed with an extra bridge connecting the 2′ and 4′ carbons.
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