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Protein epitope mimetic macrocycles as biopharmaceuticals
1 2 1 1
Anatol Luther , Kerstin Moehle , Eric Chevalier , Glenn Dale
1 and Daniel Obrecht
Fully synthetic medium-sized macrocyclic peptides mimicking past 15 years [5,6,7 ], these examples are not an indication
b a
the key -hairpin and -helical protein epitopes relevant in many of a generalized successful approach.
protein–protein interactions have emerged as a novel class of
drugs with the potential to fill an important gap between small So far PPIs have mostly been addressed by therapeutic
molecules and proteins.Conformationally stabilizedmacrocyclic proteins which since their very successful introduc-
scaffolds represent ideal templates for medicinal chemists to tion have constantly increased their market share [8,9].
incorporate bioactive peptide and protein pharmacophores in Particularly, therapeutic antibodies, Fc-fused therapeutic
order to generate novel drugs to treat diseases with high unmet proteins, and an increasing number of alternative protein
medical need. This review describes recent approaches to scaffolds [10,11] have emerged as powerful molecules to
design and generate large libraries of such macrocycles, for hit address targets with large surface interactions. Despite
identification, and for their efficient optimization. Finally, this the large diversity of scaffolds, the targets for therapeutic
review describes some of the most advanced protein epitope proteins are so far dominated by soluble proteins (e.g.,
mimetic (PEM) macrocycles in clinical development. cytokines: TNF-a, IL4/13, IL5, IL6, IL17 etc.; enzymes:
PCSK9) and some cell-surface proteins and receptors
(PD-1, PD-L1, CTLA-4; CD-20 etc.). In addition, thera-
Addresses
peutic proteins show limited tissue penetration, are usually
1
Polyphor Ltd, Hegenheimermattweg 125, 4123 Allschwil, Switzerland
2 not cell-permeable, and limited mainly to extracellular
Department of Chemistry, University of Zurich, Winterthurerstrasse
targets. Furthermore, therapeutic proteins have been less
190, 8057 Zurich, Switzerland
successful for modulating signaling receptors (GPCRs,
Corresponding author: Obrecht, Daniel ([email protected]) ion channels, transporters), probably due to their specific
pharmacokinetic and kinetic binding properties, and are
usually administered parenterally, being generally not
Current Opinion in Chemical Biology 2017, 38:45–51
suitable for oral and inhaled applications (Figure 1).
This review comes from a themed issue on Next generation
therapeutics Extensive efforts are currently made to overcome such
limitations by the development of novel formulation
Edited by David Craik and Sonia Troeira Henriques
strategies [12]. Therefore, it is clear that novel drug
classes that are able to address intracellular and extra-
cellular PPIs with complementary drug-like properties
to therapeutic proteins, allowing for example alternative
http://dx.doi.org/10.1016/j.cbpa.2017.02.004 administration routes such as oral and inhaled adminis-
1367-5931/ã 2017 Elsevier Ltd. All rights reserved. tration, will fill an important gap and complement the
existing drug arsenal (Figure 1).
Recently medium-sized natural and synthetic macrocycles
in the range of 500–4000 Daltons (Da) have emerged as
privileged scaffolds and a potential alternative to small
Introduction molecules and large biopharmaceuticals to address the
Despite an enormous global effort in academic and untapped target space and overcome some of the present
industrial pharmaceutical research and development, cur- limitations (Figure 1). Macrocyclic natural products for
rent drugs address only roughly 30% of the estimated example have provided important drugs, especially in
3000 disease-relevant targets [1 ,2], leaving patients and the antiinfective and oncology areas [13–15]. An analysis
doctors without appropriate treatment options for many of approved natural product-derived drugs between 1976–
fatal diseases. 2006 shows a high proportion of macrocyclic products
underscoring their importance for drug discovery and
Many of the untapped targets with potential therapeutic development [16,17].
applications are extracellular and intracellular protein–
protein interactions (PPIs), including multiprotein net- Properties of medium-sized macrocycles and
works [3,4], where binding interfaces are large and often target space
flat. Although some success stories of small molecule Medium-sized macrocycles combine two important fea-
approaches addressing PPIs have been reported in the tures [18 ]. First, their larger size as compared to small
www.sciencedirect.com Current Opinion in Chemical Biology 2017, 38:45–51
46 Next generation therapeutics
Figure 1
Medium-sized Macrocycles Route of Administration Peptides Macrocyclic Peptides Small bRo5 Small Large Molecules Macrocycles Proteins Proteins
Vancomycin Insulin Injectable Caspofungin Liraglutide Balixafortide TNF-α Avastin ALRN-6924 Murepavadin mAbs Cytokines ADCs Inhaled POL6014 Chemokines Fusion bRo5 Interferons proteins Macrocycles PEM Stapled Hormones Macrocycles Peptides Oral Cyclotides Imatinib MacroFinder Bicycles Aspirin Cyclosporin A
Rapamycin 0.5 1.0 2.0 4.0 5.0 10 100 200
Molecule Weight in kDa
Current Opinion in Chemical Biology
Medium-sized macrocycles complement the chemical space between small molecules and therapeutic proteins:
X-axis: drug molecule classes according to increasing molecule weight (MW).
Y-axis: general trends of applicable administration routes for different drug molecule classes:
- Small molecules (MW0.5 kDa): oral route is preferred (e.g., aspirin, MW: 180.16 Da), F = 68%; imatinib, MW: 493.62 Da, F = 97%).
- Beyond rule of 5 (bRo5) molecules (MW: 0.5–1.2 kDa): some molecules are also orally bioavailable (e.g., rapamycin, MW: 914.19 Da, F = 14%;
cyclosporine A, MW: 1203.64 Da, F = 30%), however, many molecules are administered parenterally (e.g., caspofungin, MW: 1093.33 Da) [25 ].
- Macrocyclic peptides, peptides (MW: 1–5 kDa): administration is generally parenterally (e.g., vancomycin; Balixafortide; ALRN-6924). PEM
macrocycles are chemically very stable and can be formulated for inhalation (e.g., POL6014). High lung and low systemic exposure allows to
minimize potential systemic side-effects.
- Small and large therapeutic proteins (5–200 kDa): administration is generally parenterally (e.g., TNF-a, avastin).
molecules allows macrocycles to bind to ‘hot spots’ behavior favoring intramolecular H-bonds in apolar envi-
[19 ,20 ] with binding sites typically in the range of ronment facilitating cell-permeation, and conformations
˚ 2
800–1200 A [21 ], and second, their conformational exposing H-bond donors important for binding to a target
semi-rigidity provides the necessary flexibility for in polar surrounding [22]. A classical representative for
induced fit [22]. The latter point is critical as many PPIs such a molecule is cyclosporin A (CsA; MW: 1204 Da)
involve dynamic surfaces [23,24]. In addition, the confor- which is orally bioavailable (Figure 1). Several other
mational adaptability of macrocycles beyond the rule of 5 examples of orally bioavailable cyclopeptides containing
(bRo5) translates into favorable physicochemical proper- N-methylated amino acids showing chameleonic confor-
ties (e.g., molecular weight (MW): 1000 Da; total polar mational behavior have also been described [29].
˚ 2
surface area (TPSA): 250 A ) as highlighted in several
recent reviews [25 ,26,27]. As a result, oral bioavailability is A number of approaches have used such structural features
observed for some natural and synthetic macrocycles that derived from the analysis of natural products to design fully
significantly violate the rule of 5 [28]. The highest restric- synthetic macrocycle libraries with good drug-like proper-
1
tions seem to be imposed by high lipophilicity and the ties(Table 1),oneexampleistheMacroFinder libraryasa
number of solvent-exposed hydrogen bond donors [26,27]. typical representative for bRo5 macrocycles with the
Some macrocycles exhibit chameleonic conformational potential of oral bioavailability [30].
Current Opinion in Chemical Biology 2017, 38:45–51 www.sciencedirect.com
Protein epitope mimetic macrocycles Luther et al. 47
Table 1
conformationally stable type-II’ b-turn template (e.g.,
D L
Pro- Pro)-induced cyclopeptide scaffold [34 ] (Figure 2).
Macrocycle-based library approaches
Integrating 4–20 amino acid building blocks into the
Approach Company/Organization
PEM scaffold allowed to synthesize hairpin mimetics
Cyclopeptides:
of different size, essentially mimicking most of the
MATCH cyclopeptides [52] Tranzyme Pharma (now
naturally occurring hairpin loops. It is interesting to note
Ocera Therapeutics)
that the PEM scaffold can also be successfully used to
Protein epitope mimetics (PEM) [34 ] Polyphor
a
Stapled peptides [45 ] Aileron Therapeutics mimic -helical epitopes as successfully exemplified
DNA-encoded cyclopeptides [18 ] Ensemble Therapeutics
with the design and synthesis of potent inhibitors of
RNA-encoded cyclopeptides [53 ] PeptiDream, Ra
the p53-HDM2 interaction [41] (Figure 2).
Pharmaceuticals
Bicyclic peptides [38] Bicycle Therapeutics,
Pepscan Alternatively, the stapled peptide approach mimics
Nacellins [54] Encycle Therapeutics a-helical conformations by means of a side-chain hydro-
Cell-permeable cyclopeptides [29] Circle Pharma
carbon linkage [42] (Figure 2). Although linear peptides
SICLOPPS [55] University of Southampton
with polar side-chains usually show very limited cell-
Cyclic cell-penetrating peptides [56] The Ohio State University
permeability, peptide-stapling coupled with chemical
Phylomer peptides [60] Phylogica
Non peptide-based macrocycles: optimization can yield helix mimetics with appreciable
DOS macrocycles [57] Broad Institute
cell-permeability [43,44]. ALRN-5281 and ALRN-6924
MacroFinder [30] Polyphor
are the first stapled peptides that entered clinical devel-
Nanocyclix [58] Oncodesign
opment (Table 2), the latter targeting the p53-HDM1/2
CMRT Cyclenium Pharma
interaction (Figure 1) [45 ].
PEM drug discovery
Among the various types of macrocycles, cyclopeptides
PEM drug discovery takes advantage of several proprie-
are particularly well-suited to modulate PPIs [31], as
tary elements that were jointly developed by the Univer-
peptides in general display better packed protein–protein J
sity of Zurich and Polyphor Ltd. The PEMfinder library
interfaces making significantly more intermolecular
was designed and synthesized by integrating bioactive
hydrogen bonds, mainly those involving the peptide
peptide and protein sequences into various PEM scaf-
backbone [32 ]. Systematic analysis of protein interfaces
folds. To this end, sequences derived from protein
reveal a large proportion of recurring secondary structure
loops, GPCR ligands, blockers and activators of ion
motifs such as b-strands [33], b-hairpins [34 ], a-helices
channels and transporters, and from host defense pep-
[35], and various turn-like loop structures [36]. Cyclopep-
tides (Figure 2) were successfully integrated into the
tides which mimic such privileged structural motifs J
PEM universe. The synthetic PEMfinder library is
should therefore be highly preferred to target PPIs J
supported by the proprietary PEMphage approach,
[37 ,38]. In recent years several novel cyclopeptide-based 7 8
where libraries of 10 –10 hairpin-like peptides are dis-
drug discovery screening and hit identification technolo-
played on the surface of filamentous phage. Screening of
gies have been developed (Table 1). J J
PEMfinder and PEMphage combined with structure-
based design has provided many excellent starting
Protein epitope mimetics (PEM) points for drug discovery projects [34 ]. It is interesting
The b-hairpin and a-helical secondary structure motifs to note that all three clinical-stage PEM compounds
have been reported to allow the most densely packed Murepavadin (POL7080), Balixafortide (POL6326) and
interfaces with proteins [39] and are key locations on POL6014 originated from pharmacophores derived from
the surface of proteins for modulating protein–protein host-defense peptides [34 ].
interaction. Many peptidomimetic approaches are based
on locking important bioactive peptide pharmacophores, PEM macrocycles can be efficiently synthesized and
such as exposed loops and b-turns [36], b-hairpins purified by a unique 576-parallel process allowing rapid
[34 ], and a-helices [35] into macrocyclic scaffolds iterative optimization of biological activity, selectivity,
[37 ] (Figure 2). Furthermore, macrocyclic cysteine-rich and ADMET properties required for progressing com-
natural peptides such as cyclotides (Figure 1) [40] and pounds through the different drug discovery stages.
conotoxins and their synthetic analogues combine several
privileged epitopes in one stable scaffold and are success- PEM drugs in clinical development
fully developed as a potential new class of therapeutics To date several PEM macrocycles and other macrocyclic
(PTG-100, Table 2). peptide mimetics are in clinical development (summary
Table 2).
One of the first and most versatile peptidomimetic
approaches is the PEM approach [34 ]. Here, a b-hairpin Murepavadin (POL7080) represents the first member
loop structure is mimicked in a chemically and of a novel class of outer membrane protein targeting
www.sciencedirect.com Current Opinion in Chemical Biology 2017, 38:45–51
48 Next generation therapeutics
Figure 2
(b)
(a)
(c)
Current Opinion in Chemical Biology
The protein epitope mimetic (PEM) approach.
Colours: a-helix backbone (red); b-hairpin backbone (cyan); pharmacophore side-chains (orange).
(a) Naturally occuring cyclic peptide inhibitor from sunflower seeds in complex with trypsin (PDB: 1SFI) and a representative solution NMR
structure of a derived peptidomimetic inhibitor [34 ].
(b) Surface exposed protein loops (e.g., antibody CDR loops, PDB: 1GIG) transplanted to a template to stabilize the bioactive conformation in a
macrocyclic peptidomimetic (NMR structure) [34 ].
(c) Crystal structure of human MDM2 bound to the p53 tumor processor transactivation domain (PDB: 1YCR) and two potent peptidomimetic
scaffolds mimicking the a-helical pharmacophore. The crystal structure of a macrocyclic b-hairpin peptide in complex with HDM2 (PDB: 2AXI) is
shown at the top right [41], and the crystal structure of a stapled peptide in complex with HDM2 (PDB: 3V3B) is shown at the bottom right [45 ].
Note that p53 is turned 180 around the vertical axis compared to the top view in order to visualize the helix staple.
antibiotics (OMPTA). POL7080 was inspired by host that POL7080 interacts with the essential outer-mem-
defense antimicrobial peptides, such as protegrin I, show- brane b-barrel transporter LptD and blocks LPS assem-
ing broad-spectrum antimicrobial activity and maintain- bly in the outer membrane [48 ]. In vitro, POL7080
ing good activity against multi-drug resistant Gram-neg- displays potent antimicrobial activity against Pseudomonas
ative pathogens, which constitute a considerable and aeruginosa (PA) with an MIC90 at 0.12 mg/L when tested
growing threat to human health [46]. However, antimi- against >1200 PA clinical isolates from various geographic
crobial peptides generally exhibit unfavorable drug prop- locations, including MDR strains. In vivo, POL7080 dis-
erties. By transferring antimicrobial peptide pharmaco- plays linear pharmacokinetics, is dose proportional with a
phores onto a 14-residue PEM scaffold, PEM libraries good penetration into the epithelial lung fluid which
were designed and synthesized [47]. Among those librar- underscores its potent in vivo activity in lung infection
ies PEM macrocycles with remarkable Pseudomonas-spe- models including XDR isolates. The favorable in vitro
cific antimicrobial activity were discovered. Further opti- and in vivo properties of POL7080 combined with an
mization led to the discovery of the clinical candidate appropriate safety pharmacology and toxicology profile
POL7080 [48 ]. Mechanism of action studies showed led to the clinical development of POL7080 (Table 2) for
Current Opinion in Chemical Biology 2017, 38:45–51 www.sciencedirect.com
Protein epitope mimetic macrocycles Luther et al. 49
Table 2
Selected macrocyclic peptides in clinical developmen
Company Compound Clinical phase Indication/disease area
Aileron Therapeutics ALRN-6924 Phase 2 Cancer
ALRN-5281 Phase 1 Metabolic diseases
Apeptico Solnatide Phase 2 Pulmonary edema, acutlung injury,
(AP-301) lung transplant rejection
Bristol-Myers Squibb PD-L1 inhibitor Phase 1 Immuno-oncology
Eli Lilly LY-2510924 Phase 2 Small-cell lung cancer, renal cell carcinoma
Polyphor Murepavadin Phase 2 Pseudomonas infections
(POL7080)
Balixafortide Phase 1 Advanced metastatic breast cancer, other oncology indications
(POL6326)
POL6014 Phase 1 Cystic fibrosis, non-cystic fibrosis bronchiectasis,
alpha-1 antitrypsin deficiency
Protagonist Therapeutics PTG-100 Phase 1 Ulcerative colitis
TM
Information from Thomson Reuters Cortellis (https://cortellis.thomsonreuterslifesciences.com) and company homepages.
the treatment of serious infections caused by PA. Cur- direct lung application in different species and is charac-
rently POL7080 is planned to enter Phase III in the first terized by sustained lung retention and a >100-fold ratio
half of 2017. of airway-to-plasma concentrations, thus maximizing its
local effect and minimizing potential side effects associ-
Excessive extracellular human neutrophil elastase ated with a high systemic exposure [59]. The favorable
(HNE) plays an important role in airway mucus hyperse- physicochemical properties combined with an excellent
cretion, sustained lung tissue inflammation, and destruc- safety pharmacology and toxicology profile led to the
1
tion leading to emphysema or chronic infection [49]. clinical development of POL6014 using the Pari eFlow
Pharmacological inhibition of lung HNE by inhalation aerosol inhaler. POL6014 is currently in Phase Ib clinical
holds great promise to provide novel and highly effective studies in CF patients and underscores the potential of
treatment options for patients with airway neutrophilic PEM macrocycles for the treatment of serious lung
diseases like cystic fibrosis (CF), non-cystic fibrosis bron- diseases.
chiectasis (NCFB), alpha-antitrypsin deficiency (AATD)
or chronic obstructive pulmonary disease (COPD). The chemokine receptor CXCR4 and its ligand CXCL12
Although the target elastase and its role in lung function (SDF-1a) are key regulators of hematopoetic stem cell
deterioration has been known for many years, no suitable and cancer cell growth and migration. Inhibition of
oral small molecule compound has been identified or CXCR4 is being clinically used to harvest hematopoetic
brought to the market yet, possibly because of limited stem/progenitor cells from the bone marrow. The
lung exposure or safety. CXCR4/CXCL12 axis has also an important role in tumor
growth and metastasis, is critically involved in cancer cell-
POL6014 is a novel potent and fully reversible HNE tumour microenvironment interaction, and angiogenesis.
J
inhibitor and originated from PEMfinder library hits Inhibitors of CXCR4 have shown promise as novel cancer
inspired by the natural sunflower trypsin inhibitor (SFTI) therapeutics in combination with standard chemothera-
[34 ] (Figure 2). The PEM approach was applied to peutics against various cancer types [50] such as breast
optimize potency, selectivity, ADME and physicochemi- cancer [51]. Balixafortide (POL6326) is a potent and
cal properties in rapid iterative cycles to finally identify selective PEM CXCR4 antagonist that was inspired by
POL6014 as a suitable clinical candidate [34 ]. POL6014 the hairpin-shaped host defense peptide Polyphemusin II
potently inhibits HNE in vitro (IC50 = 1.4 nM) [34 ] and isolated from the American horseshoe crab [34 ].
also ex-vivo in the bronchoalveolar lavage from CF, POL6326 is well tolerated and in Phase Ib for combina-
AATD, and NCFB patient sputa with comparable activ- tion therapy in advanced metastatic breast cancer
ity to the endogenous alpha-1 antitrypsin. POL6014 also (Table 2).
shows significant efficacy in different rodent models
induced with exogenous NE (e.g., acute lung injury Summary and outlook
model) or endogenous NE (lipopolysaccharide and In recent years fully synthetic medium-sized macrocycles
tobacco smoke) induced models by local administration have emerged as a potential novel class of biopharma-
with ED50 0.3 mg/kg [34 ]. POL6014 shows favorable ceuticals able to address complex biological targets
solubility and stability compatible with deep lung including PPIs. By virtue of addressing a complementary
(alveoli) respirability after aerosolization. A favorable target space and exhibiting complementary physico-
pharmacokinetic profile was observed for POL6014 after chemical properties compared to either small molecules
www.sciencedirect.com Current Opinion in Chemical Biology 2017, 38:45–51
50 Next generation therapeutics
12. Mitragorti S, Burke PA, Langer R: Overcoming the challenges in
and therapeutic proteins, macrocycles may well fill an
administering biopharmaceuticals: formulation and delivery
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Conflict of interest
16. Wessjohann LA, Ruijter E, Garcia-Rivera D, Brandt W: What can a
Anatol Luther, Eric Chevalier, Glenn Dale and Daniel chemist learn from nature’s macrocycles?-A brief, conceptual
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Obrecht are employees of Polyphor Ltd, Switzerland.
Kerstin Moehle is an employee of the University of 17. Ganesan A: The impact of natural products upon modern drug
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Zurich and a part-time employee of Polyphor Ltd.
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We thank Dr. Christian Bisang for his contributions, Prof. John A. Robinson Important overview on the relevance of macrocycles in drug discovery.
(University of Zurich) and Prof. Brian Cox (University of Sussex) for proof-
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www.sciencedirect.com Current Opinion in Chemical Biology 2017, 38:45–51