Biomedical Engineering Reference
In-Depth Information
inhibitors that carry a group (e.g. a radioactive or fluorescent tag) which can be
observed live.
116,117
In this context, LeBeau et al.
116
synthesized the modified
peptide-boronic acid inhibitor 9.24 of KLK3/PSA (Ser-Ser-Gln-n(boro)-L) in
such a way that the N-terminus carries a group that chelates rhenium (Re) ions.
Re was used as a
99m
Tc analog due its similar size and polarity. Indeed, the
bulky metal ion along with the ligands did not change the anity of the inhi-
bitor for KLK3/PSA that could be exploited for the diagnosis of prostate
cancer by PET or SPECT-based imaging methods.
Another very recent approach that can be applied for in vivo imaging based on
KLK3/PSA exploits gold nanoparticles (AuNPs).
118
In this case, thiol-
terminated (through Cys) KLK3/PSA recognition peptides (His-Ser-Ser-Lys-
Leu-Gln-Cys) were synthesized and conjugated at the N-terminus with either a
near-infrared dye (Quasar 670), to enable detection in vivo, or a dark quencher
(BHQ2). Both peptides containing either the dye or the quencher were used to
decorate 20 nm AuNPs through their free thiol group at their C-terminus. Both
the AuNP and the dark quencher quenched fluorescence emitted by the Quasar
670 dye. Upon protease action, the dye is released and monitored as fluorescence
emission.
118
This type of nanoparticle was tested only with trypsin and uPA, but
similar approaches are expected to findmore andmore applications in the future.
9.4.4 KLK7 Inhibitors
KLK7 is considered to play a role in deregulated epidermal desquamation and
inflammation, characteristic features of NS, atopic dermitis, rosacea, psoriasis,
and other skin diseases. As a result, development of KLK7-specific inhibitors
has been an intense field of study. The KLK7-targeting compounds may be the
active ingredients of future pharmaceutical products or cosmetics. At Novartis
Institutes for Biomedical Research, a class of organic molecule with the general
structure 9.25 shown in Figure 9.4 was developed as KLK7 inhibitors exhi-
biting IC
50
between 1 nM and 10 mM. For example, 9.26 {(1S,2S,5R)-3-aza-
bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-[(7-chloro-naphthalen-1-ylme-
thyl)-amide] 2-[(pyridin-3-ylmethyl)-amide} has an IC
50
of 3 nM. Compound
9.27 has been used to test the recovery of skin-barrier disruption after stripping
mouse skin with S-Sqame skin sampling disks where it exhibited enhanced
recovery. In addition, it displayed anti-inflammatory activity in the TPA
(phorbol 12-myristat-13-acetate)-induced irritant dermatitis model in mice.
Also, compound 9.28 showed anti-inflammatory activity in the DNFB model
of allergic contact dermatitis in swine.
119
The heterocyclic compounds 9.29, 9.30,and9.31 are also KLK7-specific
inhibitors with an IC
50
of 20, 50, and 100 nM, respectively. Compound 9.31
was used in KLK7-transgenic mice suffering from increased skin inflammation,
hyperkeratosis, itching that becomes more frequent with age, and increased
epidermal thickness. The external application of 9.31 in KLK7-transgenic mice
resulted in an improvement
in TEWL (transepidermal water loss) with
approximately half
the
eciency of betamethasone
(Betnovat, Glaxo
