Biomedical Engineering Reference
In-Depth Information
such as acetylsalicylic acid, were applied. A general feature, however, has been that small molecules
have been used either in a random manner or at best in a case-by-case fashion, therefore Schreiber
and others decided to systematize the application of small molecules in studies of proteins. This has
led to the conception of chemical genetics.
4.2.2.1 Chemical Genetics
Chemical genetics is a research method that uses small molecules to perturb the function of proteins
and does this directly and in real time, rather than indirectly by manipulating their genes. It is used
to identify proteins involved in different biological processes, to understand how proteins perform
their biological functions, and to identify small molecules that may be of therapeutic value.
The term “chemical genetics” indicates that the approach uses chemistry to generate the small
molecules and that it is based on principles that are similar to classical genetic screens. In genetics
two kinds of genetic approaches, forward and reverse, are applied, depending on the starting point
of the investigation. A classical forward genetic analysis starts with an apparent physical character-
istic (phenotype) of interest and ends with the identii cation of the gene or genes that are responsible
for it. In classical reverse genetics, scientists start with a gene of interest and try to i nd what it does
by looking at the phenotype when the gene is mutated. In chemical genetics, small molecules are
used to perturb protein function: in forward chemical genetics, a ligand that induces a phenotype
of interest is selected, and the protein target of this ligand is identii ed. In reverse chemical genet-
ics, small molecules are screened for effects at the protein of interest, and subsequently a ligand is
used to determine the phenotypic consequences of perturbing the function of this protein. Chemical
genetics can therefore be regarded as a fruitful and complementary alternative to classical genetics
or to the use of RNA-based approaches, such as RNA interference (RNAi) technology.
A now classical example illustrating the power of small molecules in elucidating protein targets
is FK506 (or Fujimycin, Figure 4.4), which is a macrolide natural product structurally related to
rapamycin (see Chapter 6), and is currently used as an immunosuppressant after organ transplan-
tation. The target of FK506 was not known, but using FK506 as molecular bait to i sh its binding
protein from biological samples, a protein was identii ed, called FK506 binding protein (FKBP). It
OH
O
H
3
CO
HO
N
CH
3
H
3
CO
OH
Galanthamine
O
H
3
C
O
OH
O
N
N
O
CH
3
O
O
HO
CH
3
O
O
S
Br
H
3
C
OCH
3
H
OCH
3
OH
NH
OCH
3
FK506 (Fujimycin)
Secramine
FIGURE 4.4
Examples of compounds used in chemical genetic studies. FK506 was used to identify its
protein target, FKBP. Galanthamine was employed as a template for the DOS of structurally diverse analogs,
which lead to the identii cation of secramine, as an inhibitor of vesicular trafi c out of the Golgi apparatus.
