Biomedical Engineering Reference
In-Depth Information
Table 5.1 Comparative overview of DPP-4 and FAP.
DPP-4
FAP
Enzyme
activity
Dipeptidyl peptidase
Dipeptidyl peptidase and
endopeptidase
Distribution
Ubiquitous in normal tissue. Upregu-
lated in certain cancers
Restricted—only in
remodelling tissue
Physiological
substrates
GLP-1, GIP, SDF-1a, SDF-1b,
Substance P
a2-antiplasmin, dena-
tured type I collagen
Cellular
localisation
Cell surface, cytoplasmic and soluble
Cell surface, cytoplasmic,
and soluble
Ligands
Adenosine deaminase, glypican-3,
Sodium hydrogen exchanger isoform 3,
plasminogen 2e, fibronectin, CARMA1
uPAR, integrin b1
Gene knockout
mouse
phenotype
Improved glucose tolerance and resis-
tance to obesity. Less liver fibrosis
Improved glucose toler-
ance on high-fat diet.
Less liver fibrosis
The unique distribution of fibroblast activation protein (FAP), the closest
relative of DPP-4, has led to numerous investigations of it as a target and
marker for epithelial cancers. The roles of the newer members, DPP-8 and
DPP-9, are yet to be fully characterized, but early evidence suggests possible
roles in various aspects of cell biology and disease.
1
There are a number of favorable factors that have contributed to the ther-
apeutic approaches of targeting DPP-4 and FAP.
1
Specific targeting of DPP-4
and FAP is made easier by the small size of this enzyme family and some
structural differences at their active sites. Additionally, observations over the
past decade that the DPP-4 and FAP gene knockout (gko) mice are healthy
(Table 5.1) suggests that selective inhibition of each of these proteases would be
safe, and this is reflected in the excellent safety profiles of the DPP-4-selective
gliptins.
2
These proteins also have interesting extra-enzymatic activities that are
expected to be retained in the presence of protease inhibition.
3,4
This feature
also points to a low likelihood of off-target effects. Thus, an overall under-
standing of DPP-4 and FAP structure-function relationships, distribution, and
enzymatic and extra-enzymatic biological roles provides an insight into their
therapeutic usefulness as disease targets.
5.2 DPP-4
5.2.1 Functions of DPP-4
DPP-4 is the prototype of the dipeptidyl peptidase-4 family of enzymes. It has
the unique ability to cleave a prolyl bond two positions from the N-terminus of
a peptide. Proline is an unusual residue with a cyclical chemistry. The presence
of proline in a peptide confers resistance against general protease degradation,
so the specialized ability of DPP-4 family proteases to cleave the post-proline
