163acts as a scaffolding or template for folding rather than as a competitive antagonist.
These fi ndings present therapeutic opportunities for HH and other disorders result-
ing from protein misfolding. A synthetic antagonist has been used successfully in
clinical trials to rescue receptor protein misfoldings in nephrogenic diabetes insipi-
dus, in which improper reabsorption of water in the kidneys leads to various meta-
bolic disorders.
The potential of chemical chaperones to treat chronic liver disease and emphy-
sema has been established as both diseases can be caused by misfolding of the
alpha-1-antitrypsin (alpha-1-AT) inhibitor. When the mutant protein is retained in
the liver cells rather than secreted into the blood and body fl uids, it is thought to
become toxic to the liver. Its depletion in the lung causes emphysema via failure to
block an enzyme that hydrolyzes the connective tissue elastin. A drug,
4- phenylbutyric acid (PBA), which was shown to be was effective on mice trans-
genic for the human alpha-1-AT gene, has been safely administered in clinical trials
to children with disorders of the urea cycle.
Proteomic Technologies for Drug Discovery and Development
Proteomic technologies are now being integrated into the drug discovery process as
complimentary to genomic approaches. This offers the scientists the ability to inte-
grate information from the genome, expressed mRNAs and their respective proteins
as well as subcellular localization. By focusing on protein activity levels, or expres-
sion levels, researchers are able to learn more about the role proteins play in causing
and treating disease. Proteomics also aids in deciphering the mechanisms of disease
and increasing both the opportunity to develop drugs with reduced side effects and
an increased probability of clinical trial success. Proteomics has the potential to
increase substantially the number of drug targets and thereby the number of new
drugs. Automation of proteomics on a scale similar to that used for genome sequenc-
ing may be needed and this is feasible by adapting the many tools already developed
for genomics for application to proteomic technologies. Application of proteomic
technologies has enabled the prediction of all possible protein-coding regions and to
choose the best candidates among novel drug targets. Proteomics technologies are
useful for drug discovery. By helping to elucidate the pathomechanism of diseases,
proteomics will help the discovery of rational medications that will fi t in with the
future concept of personalized medicines. A detailed description of various pro-
teomic technologies for drug discovery is given in a special report on proteomics
(Jain 2015 ). A few examples are given here.
Pharmacoproteomics helps to determine the mechanisms of action of bioactive
molecules in a systems pharmacology context. In contrast to traditional drug dis-
covery, pharmacoproteomics integrates the mechanism of a drug’s action, its side
effects including toxicity, and the discovery of new drug targets in a single approach
(Hess 2013 ). This approach facilitates personalized drug discovery.
Proteomic Technologies for Drug Discovery and Development