Privileged scaffolds targeting reverse-turn and helix recognition

Article (PDF Available)inExpert Opinion on Therapeutic Targets 12(1):101-14 · February 2008with40 Reads
DOI: 10.1517/14728222.12.1.101 · Source: PubMed
Abstract
Protein-protein interactions dominate molecular recognition in biologic systems. One major challenge for drug discovery arises from the very large surfaces that are characteristic of many protein-protein interactions. To identify 'drug-like' small molecule leads capable of modulating protein-protein interactions based on common protein-recognition motifs, such as alpha-helices, beta-strands, reverse-turns and polyproline motifs for example. Many proteins/peptides are unstructured under physiologic conditions and only fold into ordered structures on binding to their cellular targets. Therefore, preorganization of an inhibitor into its protein-bound conformation reduces the entropy of binding and enhances the relative affinity of the inhibitor. Accordingly, this review describes a general strategy to address the challenge based on the 'privileged structure hypothesis' [Che, PhD thesis, Washington University, 2003] that chemical templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as small-molecule inhibitors of protein-protein interactions. The authors highlight recent advances in the design of privileged scaffolds targeting reverse-turn and helical recognition. Privileged scaffolds targeting common protein-recognition motifs are useful to help elucidate the receptor-bound conformation and to provide non-peptidic, bioavailable substructures suitable for optimization to modulate protein-protein interactions.
Review
10.1517/14728222.12.1.101 © 2008 Informa UK Ltd ISSN 1472-8222 101
General
Privileged scaffolds targeting
reverse-turn and helix
recognition
Ye Che & Garland R Marshall
Washington University, Center for Computational Biology and Department of Biochemistry and
Molecular Biophysics, St. Louis, MO 63110, USA
Background : Protein–protein interactions dominate molecular recognition in
biologic systems. One major challenge for drug discovery arises from the very
large surfaces that are characteristic of many protein–protein interactions.
Objectives : To identify ‘drug-like’ small molecule leads capable of modulating
protein–protein interactions based on common protein-recognition motifs,
such as α -helices, β -strands, reverse-turns and polyproline motifs for example.
Overview : Many proteins/peptides are unstructured under physiologic
conditions and only fold into ordered structures on binding to their cellular
targets. Therefore, preorganization of an inhibitor into its protein-bound
conformation reduces the entropy of binding and enhances the relative
affinity of the inhibitor. Accordingly, this review describes a general
strategy to address the challenge based on the ‘privileged structure
hypothesis’ [Che, PhD thesis, Washington University, 2003] that chemical
templates capable of mimicking surfaces of protein-recognition motifs are
potential privileged scaffolds as small-molecule inhibitors of protein–protein
interactions. The authors highlight recent advances in the design of
privileged scaffolds targeting reverse-turn and helical recognition.
Conclusions : Privileged scaffolds targeting common protein-recognition
motifs are useful to help elucidate the receptor-bound conformation and to
provide non-peptidic, bioavailable substructures suitable for optimization
to modulate protein–protein interactions.
Keywords: drug discovery , helix , interaction , privileged structure , protein–protein reverse turn
Expert Opin. Ther. Targets (2008) 12(1):101-114
1. Introduction
Protein–protein interactions are central to many key biologic pathways and, thus,
are attractive targets for drug discovery [1-6] . However, developing small molecules
that modulate protein–protein interactions is generally considered difficult. The
challenge with protein–protein interaction sites, is that the interaction surface
involved is between 750 – 1500 Å
2
, vastly exceeding the potential binding area
of a low molecular weight compound. At first glance, trying to modulate an
interaction of this type with a typical ‘rule of five’-compliant small molecule [7]
appears incredibly difficult to many people at first glance. Thus, protein–protein
interactions have become known as ‘hard targets’ and have often been
dismissed in the past as ‘undruggable’. The key question in this field was
whether any systematic approaches for inhibiting protein–protein interactions
could be developed.
Recent studies of protein interactions involved in cell regulation and signaling
have identified a large number in which one component involves a flexible or
unstructured region of the polypeptide chain under physiologic condition that
1. Introduction
2. Reverse-turn recognition
and mimicry
3. Helix recognition and mimicry
4. Expert opinion
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Privileged scaffolds targeting reverse-turn and helix recognition
102 Expert Opin. Ther. Targets (2008) 12(1)
folds into ordered structures only on binding to their cellular
targets [8-16] . In addition, database analysis indicated that
there was a high abundance of intrinsic disorder in signaling
proteins, as well as in proteins associated with cancer,
neurodegenerative diseases and cardiovascular diseases
[17,18] .
Coupled folding and binding often gives a protein
complex with high specificity and relatively low affinity,
which is appropriate for signal transduction proteins that
must not only associate specifically to initiate the signaling
process, but must also be capable of dissociation when
signaling is complete. Nature optimizes rates and system
dynamics rather that affinities per se . Another advantage of a
system that uses components that fold on binding is that
the conformational flexibility facilitates the post-translational
modifications of proteins [19,20] . Conformational flexibility
allows a protein to bind to both its physiologic target and
to modifying enzymes. It has been shown that regions
undergoing disorder-to-order transitions during interaction
with binding partners are very common in signaling proteins
and the concept of molecular recognition features was pro-
posed to account for these regions [21] . The thermodynamic
consequence is that there is an entropic cost associated with
the disorder-to-order transition that accompanies the binding
of an intrinsically unstructured protein to its target. It is
estimated (see Mammen et al. [22] for a thorough discussion
of torsional entropy) that elimination of a single rotational
degree of freedom of a peptide by preorganization to
stabilize the receptor-bound conformation enhances affinity
by 1.2 – 1.6 kcal/mole assuming complete (unlikely at
physiologic temperatures) loss of rotational degrees of
freedom [23] . Thus, preorganization of an inhibitor into its
protein-bound conformation should reduce the entropy of
binding and potentially enhance the binding affinity by
orders of magnitude. Therefore, it has been proposed
that intrinsically disordered proteins represents a novel
type of drug targets and protein–protein interactions
involving one disordered partner are, perhaps, more
drugable sites of interaction that can be used to fill drug
discovery pipelines [1,6,24] .
In fact, the recognition of peptide hormones by their
receptors can be viewed as a special case of protein–protein
interactions involving one unstructured partner. It has been
a topic of interest ever since du Vigneaud and co-workers
[25]
first explored the chemical basis of specificity of the non-
apeptide hormones oxytocin and vasopressin. While peptides
have wide therapeutic application, they are often limited
because of undesirable absorption, distribution, metabolism
and excretion properties, undesired side effects due to
undesirable interactions of conformationally flexible peptides
with non-targeted receptors [26] . This has led to the concept
of peptidomimetics, compounds which have different, and
often conformationally constrained, chemical structures that
still maintain the ability to interact with a specific peptide
receptor [27] . Often, peptidomimetics arise from chemically
significant modifications of existing peptides or by the use
of rigid non-peptidic scaffolds with only limited flexibility,
in order to imitate the three-dimensional structure of a
peptide in its receptor-bound conformation as closely as
possible. This reduction in the decrease of freedom may
eventually lead to receptor binding with high affinity because
of entropic reasons, provided that the receptor binding is
not compromised in the modified peptide. One example
was the design of a series of cyclic, conformationally
restricted analogs of somatostatin, an inhibitor of hormone
receptors. One of the potent analogs, a cyclic octapeptide,
exhibited high affinity (the potency is 7800 times
somatostatin) and selectivity for µ-opiate receptor
[28] .
Octreotide, a cyclic peptide analog of somatostatin, has been
approved for the treatment of acromegaly and of patients
with metastasizing carcinoid and vasoactive tumors [29] .
From the authors’ perspective, the best place to look for
small molecules that interfere with protein–protein inter-
actions are peptidomimetics; chemical scaffolds that mimic
the most common protein recognition motifs. By suitable
decorating such chemical scaffolds, they are able to provide
ligands for multiple, unrelated classes of protein targets with
high affinity. Therefore, these chemical scaffolds can be
viewed as privileged structures [30] that provide the medicinal
chemist with common, non-peptidic, orally available sub-
structures as suitable starting points in combinatorial
synthesis. Common protein recognition motifs comprise
repetitive structures, such as α -helix or β -sheet and non-
repetitive structures, such as a reverse-turn or loop. This
review highlights recent advances in the design of privileged
scaffolds targeting reverse-turn and helical recognition.
2. Reverse-turn recognition and mimicry
A reverse-turn is a structural motif that invariably lies on the
surface of proteins that often participates in protein–protein
interactions [31] . Receptor recognition, substrate specificity
and catalytic function generally reside in these loop
regions, which often connect residues of adjacent α -helices
and β -strands, contributing to the structural stability of
proteins. Reverse-turns comprise a diverse group of
structures with a well-defined three-dimensional orientation
of amino acid side chains. β -Turns constitute the most
important subgroup and are formed by four consecutive
amino acids. Examples of turns as recognition motifs
can be readily found in peptide antigen–antibody
complexes [32] . Structure–activity relationship studies of
many peptide hormones interacting with G-protein-coupled
receptors (GPCRs) have indicated that the hormones
are probably in reverse-turn conformations when bound to
their receptors [33,34] .
2.1 Non-peptidyl reverse-turn mimetics
It is desirable to have a repertoire of scaffolds that reliably
transform the information present in reverse-turn motifs,
seen in proteins, into non-peptidyl compounds of low
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Che & Marshall
Expert Opin. Ther. Targets (2008) 12(1) 103
molecular weight. The desired reverse-turn conformation
should be imitated as closely as possible and the synthetic
route for the non-peptidyl mimetic should permit the
introduction of appropriate side chains onto the mimetic
scaffold. Thus, the mode of action of a biologically active
peptides on the protein target can be imitated by the small
molecule (agonist) or can be blocked (antagonist). Today,
such compounds – that combine bioavailability and stability
superior to that of bioactive peptides with increased
receptor selectivity – are the subject of major interest by
pharmaceutical companies.
Examples of privileged structures used to mimic
reverse-turn motifs include, for instance, the benzodiazepine
(
Figure 1 ( 1 )) scaffolds [30,35,36] . The benzodiazepine ring is a
core element of a natural product, asperlicin, which was
discovered during a screening of fungal metabolites and was
found to be a cholecystokinin A (involved in the control of
appetite) antagonist [37] . Asperlicin was combined with a
D-Trp structural motif, culminating in the synthesis of a
selective orally administered peptidomimetic antagonist of the
peptide hormone cholecystokinin [38] . The benzodiazepine
derivatives continue to generate leads against multiple
protein receptors [39-43] . The benzodiazepine scaffold, which
is probably the best known privileged platform, has also
produced farnesyl transferase inhibitors, reverse transcriptase
inhibitors and ligands for the HIV-1 Tat protein [44] , in
addition to leads for GPCRs and ion channels. This use
in targeting peptide receptors is rationalized by the ability of
benzodiazepines to mimic the entire set of classical β -turns
in its ability to orient four side chains (Ripka et al. [24] ,
Hata et al. [25] ).
Monosaccharides provide an excellent platform to tailor
molecular diversity by appending desired substituents at
selected positions around the sugar scaffold ( Figure 1 ( 2 )).
It was Hirschmann et al. [45,46] , who conduced the
pioneering work and demonstrated the use of β - D-glucose as
a scaffold in the synthesis of somatotropin release-inhibiting
factor peptidomimetics targeting somatostatin receptors.
Three residues, Phe-Trp-Lys, contain the necessary functional
information, but it is the relative positioning of these side
chains that determine the affinity and selectivity for one
or more of the five subtypes of somatostatin receptors.
Substituents mimicking these amino acid side chains were
positioned on a β -
D-glucose scaffold in a way that ensure
the distances between the pharmacophoric groups were
similar to those of somatostatin. Hirschmann et al. [47]
later showed that compounds with modulated receptor
subtype affinity are obtained by altering stereochemical
centers in the scaffold. D-Glucose, L-glucose and L-mannose
structural isomers were synthesized and displayed different
subtype selectivity for somatostatin receptors. Kessler and
co-workers [48] also employed the carbohydrate scaffold to
develop ligands for the integrin family. Starting from identi-
fying a bioactive cyclic peptide and NMR determination of
bioactive peptide conformations, molecular modeling was used
to design a small set of mimetics based on β -
D-mannose.
This led to the identification of α
4
β
1
-selective integrin
antagonists. Carbohydrate-like scaffolds are being used
increasing in drug design: scaffolds, such as tetrahydrofuran
rings from
D-mannitol [49] , artificial amino pyranose
rings [50] and the chemically more challenging natural
glycosides, such as β -mannoside, have been explored
(see recent reviews [51-55] ).
Numerous additional non-peptidyl systems have been
designed to mimic different types of reverse-turns. Of parti-
cular interest has been the replacement of a dipeptide motif
in a given bioactive peptide with a constrained or rigidified
counterpart ( Figure 1 ( 3 )). Freidinger et al. [56] have prepared
an analog of luteinizing hormone-releasing hormone
containing a γ -lactam as a conformational constraint. The
analog was more active as a luteinizing hormone-releasing
hormone agonist than the parent hormone and provided
evidence for a bioactive conformation containing a β -turn.
The attachment of one or more rings to the basic Freidinger
lactam structure was also possible. Fused lactam [57-61] ,
spirolactam bicyclic [62] and tricyclic [63] systems were all
examples that partially constrained the four backbone
torsion angles of residues i + 1 and i + 2 and enhance
reverse-turn propensity. By its very nature, such a motif
could also encompass heteroatom analogs, in which carbon
is replaced by sulfur, oxygen or nitrogen, at different
synthetically attainable sites. The presence of functional
groups as pendant substituents on the lactam ring system or
its heteroatom congeners also provides opportunities for
additional diversification.
2.2 Conformationally constrained peptides
for reverse-turn mimicry
Conformational and topographical restrictions are particularly
suited as manipulation for reverse-turn mimicry towards
an increase of receptor selectivity, metabolic stability and the
development of highly potent agonists or antagonists. One
straightforward approach for peptide modification is to
introduce a covalent linkage between residues i and i + 3,
such as head-to-tail cyclization, which retaining the reverse-
turn conformation. Cyclic peptides form a large class of
naturally occurring or synthetic compounds with a variety
of biologic activities, such as hormones, antibiotics, ion-
transport regulators, toxins for example. They have been
reported to bind multiple, unrelated classes of receptors with
high affinity. Thus, cyclic peptides are considered to be
privileged structures capable of providing useful ligands
for more than one receptor, due to their high content of
reverse-turn motifs. Another approach is to incorporate
heterochiral dipeptides as residues i + 1 and i + 2. Nearly all
biologic polymers are homochiral: all amino acids coded
and incorporated by protein synthesis are left-handed;
whereas all sugars in DNA/RNA and in metabolic pathways,
are right-handed. It is the homochirality of naturally
occurring amino acids that allows proteins to adopt
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Privileged scaffolds targeting reverse-turn and helix recognition
104 Expert Opin. Ther. Targets (2008) 12(1)
regular conformations, such as the α -helix and the β -sheet.
The incorporation of heterochiral (D,L-alternating)
dipeptides into a peptide chain abruptly changes the
direction of the peptide. For example, Marshall and
co-workers [64,65] suggested that D-Pro-L-Pro, L-Pro-D-Pro,
D-Pro-L-Pip, L-Pro-D-Pip, D-Pro-L-NMe-AA and
L-Pro-D-NMe-AA (where AA: amino acid other than Gly;
Pip: pipecolic amino acid; NMe: N -methylation) offer
1
2
4
5
6
7
8
3
O
O
O
O
R
2
O
R
3
R
1
R
4
N
Z
HN
NH
2
HN
O
R
1
O
R
4
HO
2
C
O
R
2
R
3
N
H
HN
NH
N
H
N
H
R
1
R
3
R
4
R
2
O
O
O
O
O
N
N
O
H
2
N
R
1
R
3
R
2
R
4
O
OH
N
N
O
O
N
N
O
O
R
1
N
N
R
3
N
N
R
2
N
Mn
H
H
Cl
H
H
Cl
Re
N
N
N
S
R
1
O
R
2
O
R
O
R
3
O
Cu
N
N
NH
2
N
R
1
O
R
2
O
R
3
O
R
4
H
2
NOC
i
i + 3
i + 2
i + 1
Figure 1 . Privileged scaffolds for reverse-turn recognition: benzodiazepines ( 1 ), sugars ( 2 ), lactams ( 3 ), cyclopentapeptides
with heterochiral dipeptide segments ( 4 ), cyclotetraprolines with chimeric amino acids ( 5 ), metal complexes of linear
peptides ( 6 ), metal ion-induced distinctive array of structures ( 7 ) and metal complexes of chiral azacrowns ( 8 ).
relatively rigid scaffolds on which to orient side chains for
interactions with receptors that recognize reverse-turn
structures. Similarly, Gellman and co-workers [66,67] described
that the β -amino acid heterochiral dinipecotic acid segments,
R-Nip-S-Nip and S-Nip-R-Nip (where Nip: nipecotic acid),
could also promote reverse-turn formation. Smith et al. [68]
also demonstrated that heterochiral pyrrolinones preferentially
adopt a turn structure.
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Che & Marshall
Expert Opin. Ther. Targets (2008) 12(1) 105
Kessler et al. [69] first established the concept of
spatial screening’ ( Figure 1 ( 4 )), whereby small libraries of
cyclic heterochiral penta- and hexapeptides as conforma-
tional scaffolds for probing receptor recognition, where a
recognition motif (such as Arg-Gly-Ser or Leu-Asp-Thr
tripeptide segments for integrin receptors) were systemati-
cally shifted around cyclic peptide–backbone structures
containing different chiralities to sample different three-
dimensional presentations of pharmacophoric side chain
groups, ultimately yielding compounds with nanomolar
affinities and high selectivity
[70-73] . The Kessler group in
collaboration with Merck KgaA has used the results from
the ‘spatial screening’ with constrained cyclic peptides to
guide the development of selective nanomolar non-peptide
molecule inhibitors for α
V
β
3
, α
V
β
5
and α
V
β
6
integrins [73] .
One peptidic α
V
β
3
inhibitor, c[RazaGDf(NMe)V], was
reported in Phase II clinical studies and formed the basis the
for design of nanomolar non-peptidic clinical candidates [74] .
A similar overall philosophy was employed by
Fujii et al. [75] to discover potent antagonists of C-X-C
motif receptor 4, the GPCR co-receptor that interacts
with the complex of gp120 and CD4, that blocked HIV
infectivity. Porcelli et al. [76] also used this approach to
discover a novel substance P antagonist. However, earlier
theoretical and experimental studies [77] have demonstrated
a considerable degree of conformational averaging in
NMR studies of cyclopentapeptides advocated as receptor
probes. This has stimulated Che and Marshall [78] to examine
cyclotetrapeptides (CTPs), the minimalist reverse-turn
mimetic, based on heterochiral dipeptides of chimeric amino
acids to be used as conformational templates, for instance,
c[D-Pro-L-Pro-D-Pro-L-Pro] ( Figure 1 ( 5 )), as synthetic
routes to chimeric prolines containing 2-, 3-, 4- or 5-position
substituents on proline are abundant. The presence of four
functionalized and stereochemically controlled centers on
each proline ring offers chemists ample opportunity to
custom design molecules to fit a pharmacophoric model;
libraries of such CTPs comprised of chimeric prolines would
lead to rapid identification of geometrical requirements from
compounds found active in library screening. Theoretical
studies [78] indicated that most reverse-turn motifs seen in
proteins could be mimicked effectively with a subset of
CTP scaffolds.
2.3 Use of metals for reverse-turn mimicry
Efforts have extended conventional cyclization by disulfide,
amide or carbon–carbon bonds through the use of metals
and the introduction of specific metal-binding sites in the
peptide itself. The use of a metal template as a strategy for
controlling the conformation of a short peptide to mimic a
reverse-turn motif was clearly enunciated and demonstrated
by Tian and Bartlett [79] . Peptide complexes of the Cu(II)
ion ( Figure 1 ( 6 )) were used to adopt the appropriate
conformation to mimic the Trp-Arg-Tyr segment of
tendamistat, a protein inhibitor of α -amylase. The metal
complexes oriented the triad around a β -turn in a fashion
similar to tendamistat, for which these residues are central
to binding interactions with α -amylase. These mimetics
were based on the structure of the complex of Cu(II) with
pentaglycine where the N-terminal amino group and the next
three amide nitrogens showed square-planar coordination to
the metal. Three tetrapeptides containing Trp, Arg and
Tyr residues showed 100-fold increases in inhibition in
the presence of Cu(II). One complicating factor in this
study was the dissociation of copper from the complex with
its inherent amylase–inhibitor activity. It is most desirable
that any metal complex has stability in the relevant biologic
milieu to reduce ambiguity in its mechanism of action and
to reduce possible toxicity.
Shi and Sharma [80] have developed a combinatorial
approach entitled metal-ion induced distinctive array of
structures in which the amide nitrogens of the N-terminal
two amide acids of a peptide preceding a cysteine residue
react with a rhenium reagent leading to formation of a
stable rhenium complex ( Figure 1 ( 7 )). This leads to stable
complexes with similar geometry to the Cu(II) complexes
of Tian and Bartlett. A selective inhibitor of human
neutrophil elastase [80] and a highly selective agonist of
the melanocortin-1 receptor [81] were discovered with the
metal-ion induced distinctive array of structures approach.
Marshall and co-workers [82-85] explored the use of metal
complexes of chiral azacrowns (MACs) derived from amino
acid synthons as a strategy for controlling the conformation
and fixing chiral side chains in orientations comparable with
those of reverse turns ( Figure 1 ( 8 )). Reduction of the amide
bonds to secondary amines of a cyclic peptide precursor
leads to a flexible azacrown and the flexibility can be limited
by complexation with a metal to fix the side chain
orientations into a manageable set [86] . Proof of concept of
MACs providing a novel approach to peptidomimetics
came from two examples, where the receptor-bound
conformations had been previously determined by X-ray
crystallography of peptide–receptor complexes [83] . One
MAC was designed to mimic the proposed receptor-bound
conformation of the Arg-Gly-Asp motif to the cyclic penta-
peptide, c[RGDfMeV], complexed with the α
V
β
3
integrin
receptor. And the other MAC was designed to mimic the
α -amylase-bound conformation of a Trp-Arg-Tyr β -turn
motif from tendamistat. The metal center is buried in
the middle of a MAC complex, acting like glue to keep the
pharmacophoric groups correctly oriented in their desired
directions. One must design a complex that affords the
proper geometrical orientations, but it is essential that
the metal be bound tightly so that no redox-active metals
are allowed to dissociate from the complex in vivo to
complicate bioassays with potentially toxic side effects.
Riley and co-workers [87-93] have demonstrated that MACs
possessed catalytic superoxide dismutase activity in a wide
range of MAC analogs when complexed with manganese.
These metal complexes showed reasonable thermodynamic
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Privileged scaffolds targeting reverse-turn and helix recognition
106 Expert Opin. Ther. Targets (2008) 12(1)
stabilities and excellent kinetic stability with the metal
complexes completely intact under physiologic conditions
and no metal dissociation for many hours even in the
presence of ethylene-diamine-tetra-acetic acid. Clinical
candidates for a variety of inflammation conditions, as
well as ischemia–reperfusion injury, refractory hypotension
and HIV-1 infection emerged from this class of metal
complexes
[90,94-96] . The fact that one MAC, M40403,
has successfully completed Phase I and II clinical trials
demonstrated that this class of metal complexes is relatively
safe and possesses suitable pharmacokinetic properties
(e.g., log P ) for use as pharmacologic probes and potential
therapeutic agents.
Several other groups have also used amino acid side chains
(e.g., cysteine, histidine, lysine, aspartic acid) or chemically
modified backbone to participate in specific metal ligation.
A few examples serve to further illustrate this approach.
Tamamura et al. [97-99] have shown that three peptides with
significantly different cyclic constraints, including a Zn(II)
complex, bind to C-X-C motif receptor 4. T22, a precursor
of T134, has four Cys residues making two disulfide bonds
and a β -hairpin conformation in solution. T22 (Zn), a
derivative of T22 in which the four sulfurs of the Cys
residues are bonded to Zn(II), has 4-fold the activity of T22.
T134 has a characteristic turn motif (D-amino acid-Pro)
and a disulfide bridge constraint to impose a β -hairpin
structure in solution. The Marshall group [100-103] developed
synthetic routes to modify the amide backbone to a
hydroxymate, or phosphinic acid (Ye et al. Biopolymers,
in press), group to provide multiple metal-binding sites.
Similarly, Akiyama et al. [104] had previously replaced the
amide bond with a hydroxymate in enkephalin to generate
a metal-binding site. These peptides mimic the naturally
occurring hydroxymate-containing siderophores involved
in iron transport. Combinations of these approaches
and complexation of the resulting compounds with
different metals should provide useful probes of
conformational preorganization with novel constraints for
reverse-turn recognition.
3. Helix recognition and mimicry
The helix is a common secondary structural motif in
proteins, a crucial recognition motif in many protein–protein
and protein–nucleic acid interactions. Helices are found
in proteins predominantly as α -helices, but occasionally as
3
10
-helices. 3
10
-Helices have also been implicated as
recognition motifs in a number of protein–protein
complexes [105,106] . In isolated helices, transition between
the α - and 3
10
-helical forms is facile with an estimated
energy barrier of 3 – 4 kcal/mole [107] . This is primarily
due to the fact that helix geometry of the peptide backbone
allows a single amino group to makes two weaker bifurcated
H-bonds in the transition state between the α - and
3
10
-helices. The lowness of this barrier suggests that small
peptide helices can be easily induced to bind in either
helical conformation by interaction with their receptors.
So far, helical peptidomimetics were designed primarily to
imitate α -helical recognition functions
[108] .
3.1 Nonpeptidyl a -helix mimetics
As the critical surface for α -helical recognition often involves
the side chains of residues i , i + 3 and/or i + 4 and i + 7,
along one face of the α -helix, one can design appropriate
scaffolds with limited conformations to orient attached
functional groups that closely resemble the surface of
α -helices. There are 3.6 residues per turn of an α -helix,
with a rise of 1.5 Å per residue. The characteristic axial rise
between these four key residues is 4.5 or 6.0 Å , respectively.
Looking down the helical axis, residues are projected at
-60 ° and 40 ° for i i + 3 and i i + 4 interactions,
respectively. Hamilton and co-workerss [109-113] described
a terphenyl scaffold ( Figure 2 ( 9 )) that can reasonably
imitate side chain orientations seen in α -helices in which
the 3,2 ,2′′-substituents on the phenyl rings present
functionalities in a spatial relationship that mimic the i ,
i + 3 or i + 4 and i + 7 residues on an α -helix. Comparing
the terphenyl scaffold and the ideal α -helical structure,
when the terphenyl is in a staggered conformation, the three
substituents project from the terphenyl core with similar
angular relationships and 5 – 30% shorter distances in the
characteristic rise corresponding to i i + 3 and i i + 4
interactions in a native α -helix. Proof of concept for helix
mimetics in protein–protein recognition came from success-
fully disrupting the interaction between calmodulin and an
α -helical domain of smooth muscle light-chain kinase [109] ;
inhibiting the assembly of HIV-1 gp41 and, thereby, reducing
levels of viral entry into host cells [110] ; preventing the
interaction between the proapoptotic protein Bak and
the antiapoptotic protein Bcl-xL [111,112] ; and blocking the
complex formation of the tumor-suppressor p53 with the
oncoprotein human double minute (HDM2) [113] . Based
on theoretical arguments, Jacoby [114] proposed that
2,6,3 ,5 -substituted biphenyl derivatives are protein α -helix
mimetics superimposing the side chains of the residues i ,
i + 1, i + 3 and i + 4, better than other templates with
a chiral axis, such as allene, alkylidene cycloalkane and
spirane. Similarly, scaffolds based on terephthalamide
[115] ,
piperazinyl-pyrimidone [116] , benzoylurea [117] and pyridazine
heterocycle [118] have also been described as nonpeptidyl
α -helix mimetics.
However, the terphenyl scaffold is not rigid; for example,
it adopts both right- and left-handed twists. There are
16 energetically almost equal conformers, only two of
which can mimic either of the desired α -helical side chain
orientations. Thus, the terphenyl scaffold is not optimally
preorganized in terms of α -helical mimicry, due to its
conformational heterogeneity. Based on molecular modeling,
Che et al. [108] described novel α -helix mimetics that are
more effective than the terphenyl at constraining the
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Che & Marshall
Expert Opin. Ther. Targets (2008) 12(1) 107
aryl–aryl torsion angles to those associated with structures
suitable for mimicking the α -helical twist for side chain
orientation and for superimposing those four key residues
when compared with the α - β side chain vectors of the regular
α -helix with improved root mean square deviation values.
As an example of one alternative scaffold, the terpyridyl one
is able to limit side chain orientation to a greater extent
than does the terphenyls. The computational study also
indicated that rotamer distributions around the C
α
-C
β
bonds of these helix mimetics are similar to those of
α -helices, except that the rotamer distributions show a
60 ° shift compared with those of α -helices when the mimetic
axis is superimposed on the helix axis. This change in
rotamer orientation complicates mimicry of the helix surface
as it implies that one cannot simply transfer side chains
from the helix to the aryl scaffold.
Figure 2 . Privileged scaffolds for a -helical recognition: terphenyls ( 9 ), trispyridylamides ( 10 ), a , a -dialkyl amino acids ( 11 ),
crosslinked interfacial peptides ( 12 ), H-bond surrogates ( 13 ), end-capping templates ( 14 ), b
3
-peptides ( 15 ) and peptoids ( 16 ).
i + 7
i + 4
i + 3
i
9
10
11
12
13
14
15
16
N
HN
N
N
N
N
H
O
H
O
H
O
R
3
R
2
R
1
O
O
HN
CO
R
3
R
2
R
1
O
N
HN
O
N
R
O
N
H
HN
R
O
R
CH
2
R
HN
R
i
i + 4
i + 3
i + 2
i + 1
N
H
R
*
O
*
n
*
N
*
R
O
n
N
O
H
O
N
O
S
H
H
H
peptide
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Privileged scaffolds targeting reverse-turn and helix recognition
108 Expert Opin. Ther. Targets (2008) 12(1)
The low solubility of the terphenyl scaffold has prompted
the Hamilton group [119] to develop another scaffold,
trispyridylamide (
Figure 2 ( 10 )), for α -helix mimicry. The
template adopts a preferred conformation in which all
three functional groups are projected on the same face of
the scaffold. This preorganization is accomplished through a
stabilizing bifurcated H-bonding network, as well as through
the minimization of alternative conformations. The charac-
teristic axial rise of 5.7 Å is close to that of the i i + 4
interaction in an α -helix. However, the alkoxy side chains
are rotated 45 ° out of the plane of the carboxamide
backbone. This may partially explain why trispyridylamide
derivatives only had affinity in the low µmolar range for
Bcl-xL, compared with a binding affinity of 114 nM for
a terphenyl compound and 300 nM for the 16 residue
BH3-domain peptide from the protein Bak.
3.2 Conformationally constrained a -helix motifs
A short synthetic peptide corresponding to a helical
recognition motif does not typically fold stably in isolation
and is usually flexible and conformationally disordered in
solution. Such flexible peptides present side chains in a
plethora of relative orientations increasing undesirable
interactions at multiple recognition sites. This inherent
flexibility also limits binding affinity when these peptides
bind to their targeted receptors in a unique conformation,
due to a more significant loss of entropy. Marshall and
Bosshard [120] predicted in 1972 that α , α -dialkyl amino
acids ( Figure 2 ( 11 )), such as α -aminoisobutyric acid (Aib or
α -methylalanine, MeA), would severely restrict the φ and
ψ torsion angles of that residue to those associated with
right- or left-handed helices (both α - and 3
10
-helices).
Subsequent experimental validation of that prediction is
abundant [121] . An example where α , α -dialkyl amino acids
were used to induce an α -helix of the peptide in water
that enhanced binding involves the p53/HDM2 helix
recognition: IC
50
of 5 nM for an Aib-containing peptide
and 8.7 µM for the native α -helical peptide [122] .
Alternatively, the helical structure can be stabilized
through the incorporation of covalent or noncovalent
linkages between side chains of two residues separated
in sequence, but spatially close in a helix, such as residues
i and i + 4 of an α -helix ( Figure 2 ( 12 )). Examples of
chemical linkages shown to enhance helical propensity
include: salt bridges [123] , hydrophobic interactions [124,125] ,
aromatic–charge [126] or aromatic–sulfur [127] interactions,
disulfide bonds [128,129] , lactam bridges [130-132] , hydrocarbon
staplings [133,134] , diaminoalkanes [135] , acetylenes [136] and
metal ligation between natural [137,138] and unnatural amino
acids [139,140] . These crosslinked interfacial peptides have been
demonstrated to yield a marked enhancement of peptide
helicity, stability and in vitro and in vivo biologic activity.
For example, the interaction between the proapoptotic
protein BID and the antiapoptotic protein Bcl-xL was
disrupted by a hydrocarbon-stapled helix combined with
α -methyl substituents on the two linked amino acids
[141] .
This conformationally constrained peptide segment, derived
from the helical BH3 domain of BID, was found to protease
resistant, cell-permeable and bound to Bcl-xL with a 6-fold
higher affinity than the unconstrained helix. Cellular uptake
was observed and apoptosis was activated within cells after
treatment with the stapled helix. In addition, the stapled
helix effectively inhibited the growth of human leukemia
xenografts in vivo .
Helical peptides are stabilized by extensive but weak
intrachain H-bonds; design of covalent surrogates of
intrachain H-bonds (
Figure 2 ( 13 )) reinforces the helical
structure [142,143] . Such artificial helical peptides are attractive
scaffolds for molecular recognition because the backbone
H-bond surrogate neither blocks solvent-exposed recognition
surface nor removes important side chain functionalities.
For example, one peptide analog of a human papillomavirus
peptide segment was conformationally restricted to an
α -helical structure using a hydrazone link and was shown to
have a very strong reaction with sera from women having
invasive cervical carcinoma [144] . Though the main body of
a peptide helix is stabilized by intrachain H-bonds, free
amino groups at the N-terminus and carboxyl groups at the
C-terminus of the helix do not participate in such internal
peptide H-bonding. Thus, preorganized helix-nucleating
templates ( Figure 2 ( 14 )) [145,146] have been developed in
which the orientation of the first 4 amino groups or the last
4 carboxyl groups were fixed in a rigid structure to template
helix formation and prevent fraying of either end.
3.3 Helical foldamers
Foldamers are sequence-specific oligomers, akin to peptides
and oligonucleotides that fold into well-defined three-
dimensional structures. They offer templates for presenting
complex array of functional groups in virtually unlimited
geometrical patterns and, thereby, providing attractive
opportunities for the design of molecules that bind in a
sequence- and structural-specific manner to protein
surfaces
[147] . A number of foldamers with a strong tendency
to adopt helical structures has been employed to interfere
with protein–protein interactions. Many of these are
structural variants of peptides, but are essentially stable to
most proteases. One such family of foldamers is the
poly- N -substituted glycines or ‘peptoids’ (
Figure 2 ( 15 )) on
which the amino acid side chains are appended to amide
nitrogens rather than to the α -carbons [148] . Despite the
achirality of the N -substituted glycines backbone and its loss
of amide H-bonds, peptoids containing α -chiral, sterically
bulky side chains are able to adopt stable, chiral helices with
cis -amide bonds. The periodicity of the peptoids helix is
3 residues per turn, with a pitch of 6 Å . Appella and
co-workers [149] explored the structural requirements of
peptoids optimized for inhibition of p53–HDM2
interactions. The other family of foldamers is β -peptides
( Figure 2 ( 16 )) that differ from α -peptides by one additional
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Che & Marshall
Expert Opin. Ther. Targets (2008) 12(1) 109
backbone carbon atom between the amino and carboxyl
groups [150,151] . β -peptides composed of β
3
- L-amino acids
are able to form left-handed 14-helices characterized by a
periodicity of 3.25 residues per turn with a pitch of 4.7 Å
and H-bonds between the backbone amide proton of residue
i and the carbonyl oxygen of residue i + 2. The ability to
form stable helices makes β -peptides good candidates for
mimicry of structures and functions of α -helical recognition
motifs. Schepartz and co-workers have designed adaptable
β
3
-peptide scaffolds with enhanced 14-helix structure by
neutralization of the helix macrodipole [152] that inhibited
the p53–MDM2 interaction [153] , as well as gp41-mediated
HIV-1 fusion [154] . Alternative helical structures of regular
and hybrid peptides consisting of homologous amino acids,
such as β -, γ - and δ -amino acids, have been implicated as
potential inhibitors to modulate α -helix recognition [155-158] .
4. Expert opinion
One major drug discovery paradigm often begins with a
known chemical starting point that has a desirable biologic
activity with therapeutic relevance, such as a natural substrate
or regulator; such information is not readily available if the
object is to disrupt a protein–protein interaction. However,
if the protein–protein interface consists of short continuous
recognition motifs, such as an α -helix or a reverse turn,
privileged scaffolds targeting these binding sites may serve as
lead compounds for subsequent optimization. In addition,
the concept of privileged scaffold targeting common protein
recognition motifs is highly attractive because the rational
design of new leads for many protein–protein interactions
has been limited by the lack of detailed structural informa-
tion for a particular targets. Privileged scaffolds can provide
medicinal chemists with common, non-peptidic, bioavailable
substructures as suitable starting points in parallel synthesis.
Ultimately, a single, large combinatorial library of privileged
structures might provide ligands for a whole series of
protein targets.
Although research to discover small-molecule drugs that
target protein–protein interactions is still at an early stage,
accelerated activity in this area will occur as compounds
move through clinical trials and the science and technology
base continues to develop. The prospective of developing
drugs that target biomolecules that are relatively well
validated in terms of biologic function and role in disease
is important in driving advances in this field.
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Affi liation
Ye Che & Garland R Marshall
Author for correspondence
Washington University,
Center for Computational Biology and
Department of Biochemistry and
Molecular Biophysics,
St. Louis, MO 63110, USA
Tel: +1 314 362 1567 ; Fax: +1 314 747 3330 ;
E-mail: garland@biochem.wustl.edu
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    • "Although this theory cannot be treated as a rule any longer and many exceptions can be listed, nevertheless it has become the foundation of molecular design and the concept of pharmacophores. In 2000, the concept of privileged motifs, which were formerly known as molecular moieties, which are able to construct effective ligands for diverse receptors, was further developed6465666768697071. The last decade has made this idea more popular and numerous moieties have been claimed to be privileged: benzazepinone [65], diphenylmethane, piperidine, biphenyltetrazole [65], indole [65,72], biphenyl [65,73], spiroindoline sulfonamide [65,74], spiroindanyl piperidine [74], dihydropyridine [75], and benzopyran [76,77]. "
    [Show abstract] [Hide abstract] ABSTRACT: HIV integrase became an important target for drug development more than twenty years ago. However, progress has been hampered by the lack of assays suitable for high throughput screening, a reliable crystal structure or pharmacophore. Thus, a real breakthrough was only observed in 2007 with the introduction of the first integrase inhibitor, raltegravir, into treatment. To date, the armament of integrase inhibitors is broad and covers several drugs from different classes that are under clinical trials. Among them, quinoline-based compounds and analogues occupy an important place. This review is focused on those compounds that have a quinoline scaffold and attempts to answer the question of whether quinoline is privileged for these activities. In fact, quinoline has been claimed as a privileged structure several times for different fields of activities. A closer look at its structural features may reveal the prerequisites responsible for the popularity of quinoline-based inhibitors of HIV integrase.
    Full-text · Article · Oct 2012
    • "Later this definition was updated by Patchett and Nargund [3]. Since then, several reviews deal with the concept of privileged motifs456789 and numerous molecular fragments have been described as privileged, e.g. benzazepinone [3], diphenylmethane [3], benzylpiperidine [3], biphenyltetrazole [3], indole [3,10], biphenyl [3,11], spiroindoline sulfonamide [3,12], spiroindanyl piperidine [12], 1,4-dihydropyridine [13] , 2,6-dichloro- 9-thiabicyclo[3.3.1]nonane "
    [Show abstract] [Hide abstract] ABSTRACT: Drug design is a complex issue that still lack general approach with proven reliability. Combinatorial chemistry and HTS techniques did not appear to be effort-effective. As an alternative we have the fragment based design and more recently so called the privileged structures approach. We believe that some structural subunits are especially effective in design of bioeffectors. However it is not clear what makes one molecular scaffold more privileged than another. Overall frequency of appearance of molecular scaffold in bioactive compounds or natural substances may be used as a good factor of qualitative discriminator of privileged structures. According this, the quinoline scaffold, due to its frequent appearance in bioactive substances can be regarded as a privileged structure. It is abundant in number of natural compounds such as alkaloids: quinine, camptothecin or cinchonidine. In synthetic medicinal chemistry the quinoline motif is widely exploited revealing a spectrum of activity covering anticancer, antifungal, antibacterial and antiprotozoic effects. In fact, introducing chloroquine into treatment of malaria more than 60 years ago triggered a new era of quickly developing antimicrobial drugs through nalidixic acid and fluoroquinolones. In this review we wish to explore antimicrobial quinolines as an important class of drugs from both natural and synthetic sources.
    Full-text · Chapter · Jan 2011 · The Journal of Organic Chemistry
  • [Show abstract] [Hide abstract] ABSTRACT: 5-Oxobenzo[e][1,4]diazepine-3-carboxamides were synthesized by sequential Ugi reaction-Staudinger/aza-Wittig cyclization. The pseudopeptidic backbone of the new benzodiazepine derivatives superimposed well with type I, I', II, and II' beta-turn motifs. The intermediate Ugi adducts were characterized as two conformers of the enol form by the correlation between (1)H NMR spectra and X-ray diffraction structures of model compounds.
    Article · Mar 2009
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