were built to define these groups [5]. Briefly, “class 1” PDZ
domains recognize C-terminal sequences with either a serine or
threonine at the À2 position. Similarly, “class 2” PDZ domains
bind to C-terminal sequences with a large hydrophobic or aromatic
residue at the À2 position. Finally, the consensus sequence recognized by “class 3” PDZ domains includes a negatively charged
residue at the À2 position. Other positions, such as À1 and À3,
have fewer constraints regarding the nature of the residue sidechain. Due to these small constraints, many peptides can bind
different PDZ domains [6], so achieving high specificity is expected
to be challenging.
It is also known that some PDZ domains are able to bind to
lipids. For instance, syntenin1 can interact with phosphatidylinositol phosphates with an affinity in the micromolar range [7].
2 PDZ Domains as Potential Drug Targets
PDZ domains, which are critical for regulating important
biological processes, have emerged as promising targets to treat
cancer and neurological diseases [1, 8–13]. Early inhibitors of
PDZ domains consisted of using short amino acid sequences representing the key C-terminal residues from endogenous partners.
Later, modified peptides, including thioketone and nonnatural
residues, were reported as biological tools to study PDZ domains
[14, 15]. Bivalent peptides were also shown to exhibit high affinity
for PDZ domains by simultaneously interacting with multiple PDZ
domains from the same protein [16]. In addition, TAT-derived
bivalent peptides, which contain cell permeability tags, were also
developed as efficient probes [16]. Despite their potential high
affinities, peptides may suffer from protein degradation by proteases and cell permeability issues. Thus, an appealing alternative
strategy is to develop small molecule inhibitors for oral administration that bypass these issues.
However, targeting PDZ domains may be very challenging
because this requires tackling the general problem of protein–protein interactions (PPIs). It has been shown that modulating PPIs
using small organic compounds is difficult due to the nature of the
interface [17]. In general, such interfaces are large and flat with
several small adjacent subpockets and are not expected to be easily
druggable [18, 19]. Several screening studies concluded, as
expected, that PDZ domains are mainly undruggable targets to
be modulated by small organic molecules and even fragments
[20, 21]. Indeed, the screening of fragment-like compounds is
considered a powerful tool to assess the druggability of a given
target [21]. These disappointing results are not truly surprising
from a structural point of view; the nature of the PDZ domain
binding pocket appears to be shallow with only a few putative
Rational Design of PDZ Domain Inhibitors
279
domains recognize C-terminal sequences with either a serine or
threonine at the À2 position. Similarly, “class 2” PDZ domains
bind to C-terminal sequences with a large hydrophobic or aromatic
residue at the À2 position. Finally, the consensus sequence recognized by “class 3” PDZ domains includes a negatively charged
residue at the À2 position. Other positions, such as À1 and À3,
have fewer constraints regarding the nature of the residue sidechain. Due to these small constraints, many peptides can bind
different PDZ domains [6], so achieving high specificity is expected
to be challenging.
It is also known that some PDZ domains are able to bind to
lipids. For instance, syntenin1 can interact with phosphatidylinositol phosphates with an affinity in the micromolar range [7].
2 PDZ Domains as Potential Drug Targets
PDZ domains, which are critical for regulating important
biological processes, have emerged as promising targets to treat
cancer and neurological diseases [1, 8–13]. Early inhibitors of
PDZ domains consisted of using short amino acid sequences representing the key C-terminal residues from endogenous partners.
Later, modified peptides, including thioketone and nonnatural
residues, were reported as biological tools to study PDZ domains
[14, 15]. Bivalent peptides were also shown to exhibit high affinity
for PDZ domains by simultaneously interacting with multiple PDZ
domains from the same protein [16]. In addition, TAT-derived
bivalent peptides, which contain cell permeability tags, were also
developed as efficient probes [16]. Despite their potential high
affinities, peptides may suffer from protein degradation by proteases and cell permeability issues. Thus, an appealing alternative
strategy is to develop small molecule inhibitors for oral administration that bypass these issues.
However, targeting PDZ domains may be very challenging
because this requires tackling the general problem of protein–protein interactions (PPIs). It has been shown that modulating PPIs
using small organic compounds is difficult due to the nature of the
interface [17]. In general, such interfaces are large and flat with
several small adjacent subpockets and are not expected to be easily
druggable [18, 19]. Several screening studies concluded, as
expected, that PDZ domains are mainly undruggable targets to
be modulated by small organic molecules and even fragments
[20, 21]. Indeed, the screening of fragment-like compounds is
considered a powerful tool to assess the druggability of a given
target [21]. These disappointing results are not truly surprising
from a structural point of view; the nature of the PDZ domain
binding pocket appears to be shallow with only a few putative
Rational Design of PDZ Domain Inhibitors
279