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Protein & Peptide Letters, 2018, 25, 1044-1050
OVERVIEW OF THEMATIC ISSUE
ISSN: 0929-8665
eISSN: 1875-5305

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Building on Success: A Bright Future for Peptide Therapeutics

BENTHAM Editor-in-Chief:
SCIENCE Ben M. Dunn

Yvonne Angell1,*, Mandë Holford 2,3,4,5 and Walter H. Moos6,7

1
ChemPartner, South San Francisco, CA, USA; 2Hunter College, New York, NY, USA; 3American Museum of Natural
History, New York, NY, USA; 4CUNY Graduate Center, New York, NY, USA; 5Weill Cornell Medicine, New York, NY,
USA; 6ShangPharma Innovation, South San Francisco, CA, USA; 7University of California San Francisco, San
Francisco, CA, USA

ARTICLE HISTORY
Received: September 10, 2018
Revised: October 4, 2018
Accepted: October 4, 2018
DOI:
10.2174/0929866525666181114155542
Protein & Peptide Letters
Abstract: The primary aim of this review article is to highlight current exciting and future looking
areas of research in peptide science as applied to the discovery and development of novel therapeutics.
Among the strengths of peptides as drug candidates are their high potency, specificity, and good safety
profile. These positive attributes of peptides along with advances in drug delivery technologies have
generated renewed interest in the discovery, optimization, and development of peptides as therapeu-
tics. The intent of this review is to demonstrate that peptides have broad applicability in many thera-
peutic areas by examining some of the most compelling indications and targets for peptide therapeu-
tics. For example, target selection for peptide therapeutics is challenging due to the inherent properties
of peptides; therefore, identifying a clear differentiation strategy for a new peptide program over a
small molecule or antibody program from the outset is critical for successful navigation of drug
development hurdles. In this review, some of the latest techniques that accentuate the advantages and
overcome the druggability limitations of peptides will be covered. Emerging technologies for
enhancing the pharmacokinetics of peptides to achieve sufficient in vivo half-lives will be described
and evaluated, as well as novel technologies for getting peptides across cell membranes to reach
intracellular targets and across the blood-brain-barrier to reach central nervous system targets.

Keywords: Drug discovery, oncology, peptide, potency, protein, safety, specificity, therapeutic target.

1. INTRODUCTION
Our review capitalizes on the strengths of peptides as
providing some of the latest advancements in therapeutic
peptidic hormones, targeting protein-protein interactions
especially for oncology indications, increased use of venom
peptides as therapeutics as well as diagnostics, and the po-
tential of antimicrobial peptides – all to emphasize the dis-
tinctive properties peptides have compared to other therapeu-
tic modalities (Figure 1) [1]. Peptide discovery teams face
significant challenges to propose altogether new peptide drug
discovery projects, aiming for novel molecular targets, in the
hottest therapeutic areas, with indications that will be com-
petitive with small molecules and biologics. This is true even
though peptides, large and small, have higher success rates in
progressing through development than do small molecule
non-peptide drugs. These findings were summarized recently
in a “case for peptides” [2].

2. DRUG TARGETS & PEPTIDE THERAPEUTICS

Extensive research on molecular drug targets has been
conducted for many decades in academia, government, and
other nonprofit laboratories, along with thousands of
*Address correspondence to this author at the ChemPartner, 280 Utah
Avenue, Suite 100, South San Francisco, CA, USA; Tel: 650-419-9974;
E-mail: yangell@chempartner.com
Figure 1. Peptide Therapeutics 2020 and Beyond. A sampling of
the peptide drugs featured in this Special Issue highlighting syn-
thetic, antimicrobial, and anticancer peptides, drug discovery from
venomous animals and some of the instrumentation methods used
for peptide synthesis (automated peptide synthesizer) and charac-
terization (microfluidic chips).

1875-5305/18 $58.00+.00 © 2018 Bentham Science Publishers

Building on Success: A Bright Future for Peptide Therapeutics
Table 1. Drug target estimates since the 1990s. Adapted with permission from [3].
When Estimates of Known Distinct Drug Targets
1990s < 500
2002 ~ 400
2006 > 300
2008 > 1,500
2013 ~ 1,250
2014 > 500
2014 > 2,000
2016 > 4,000
biotechnology and pharmaceutical firms. Thus, today, fewer
and fewer validated ‘novel’ targets are known to the public.
Indeed, most targets are no longer novel. This is just one of
the challenges in drug discovery, albeit not unique to pep-
tides. Estimates of numbers of distinct drug targets can be
found in Table 1 [3].
Additionally, most ‘Hot’ targets are by-and-large known,
not novel. However, there are some hot areas worth noting, a
couple of examples of which follow here, and will be dis-
cussed further below:
• Immuno-oncology (e.g., checkpoint inhibitors).
• Biased agonists of G-protein coupled receptors
(GPCRs; e.g., biased opiates devoid of classical
side effects).
A novel drug target generally refers to a target that has
not been clinically validated. This, by definition, equates a
novel drug target with high risk; however, current drug dis-
covery efforts are mainly focusing on previously validated
‘druggable’ protein families such as kinases [13]. This leaves
a vast space of the protein universe unexplored. Significant
efforts have been made to predict viable drug targets by nu-
merous industrial and academic teams. For example, there is
an urgent need for the identification and validation of new
cancer-relevant targets. Thus, to predict cancer drug targets
on a genome-wide scale, researchers developed an optimized
set of classifiers, applied them to 15,663 human proteins, and
measured the probability of each to be a suitable drug target
specific to various types of cancer [14]. Their scores repre-
sent a prioritization of potential cancer drug targets, which is
representative of their importance in cancer as measured by
the diverse features they integrated, all of this to be used as a
guideline. They identified 345 intracellular potential peptide
drug targets that have known peptide-binding domains and
are thus accessible with synthetic peptides, assuming that the
peptides can be manipulated to cross the membrane [15, 16].
It has been shown that synthetic peptides binding to Zap70,
Lck, and Src (global cancer targets) block signaling down-
stream of these proteins and induce apoptosis in cancer cells
[17, 18].
Protein & Peptide Letters, 2018, Vol. 25, No. 12 1045
Notes References
- [4, 5]
Rule-of-five-compliant only [6]
- [7]
DrugBank [8]
Human protein targets only [9]
Human genome-encoded only [10]
- [11]
DrugBank Version 5.0 [12]
We should also factor in the reality that many recent suc-
cessful peptide-based products have certain non-peptide
structural features to combat deficiencies associated with
developing peptide drugs. The non-peptide features convey
greater novelty, improve on strict peptide functionalities for
greater affinity and/or higher selectivity, and may also con-
vey better absorption, distribution, metabolism, elimination,
and/or toxicology (sometimes abbreviated as ADME or
ADMET) characteristics. Technical advances that seek to
stabilize peptide conformations include chemical innovations
such as stapling, hydrogen bond surrogates, beta-hairpin
mimetics, and synthetic ‘linchpins’ [19-21]. Peptides cy-
clized by linchpins can be viewed as a sub-class of a larger
family of peptide-derived cyclic and macrocyclic drugs. In-
terestingly, several of these stabilizing techniques being used
to minimize the limitations of peptides in drug development
are found in naturally derived peptide therapeutics. Natural
peptides such as insulin, oxytocin, and cyclosporine (all
blockbuster drugs), inherently contain engineered features
being synthetically investigated [22]. Similar to these initial
successful peptide therapeutics, peptides found in animal
venoms are highly structured with stabilized conformations
induced by cysteine-rich residues, a feature that enhances the
potential of venom peptide therapeutics.
Many successful peptide-based products employ drug
delivery strategies that increase membrane permeability or
duration of action. Specific cell-penetrating peptide se-
quences have been identified, often highly charged, which
can be used to transport peptides, proteins, and other mole-
cules across membranes [23]. In regard to drug delivery, oral
bioavailability of peptides is often no more than 2%, making
other routes of administration such as intravenous or subcu-
taneous injections the only viable path to treating a patient.
Biodegradable long-acting release matrices enabled one of
the early peptide pharmaceutical successes, namely, embed-
ding drugs such as hormone modulators in polymers or hy-
drogels. Polyethylene Glycol (PEG) conjugates have also
been used to increase half-life, as have other means of in-
creasing the duration of action of peptides and proteins, such
as the recombinant protein, XTEN [24].
1046 Protein & Peptide Letters, 2018, Vol. 25, No. 12
The difficulties of delivering peptide therapeutics is
clearly demonstrated with insulin, which is the most thor-
oughly researched peptide hormone therapeutic and the first
breakthrough peptide drug. However, it is not orally active
and has to be administered by injection. There are nearly a
hundred different insulin products on the market that vary in
chemical structure, Pharmacokinetics (PK), and pharmaceu-
tical concentration. In the article on structurally constrained
insulin analogues in this Special Issue, F. Zhang et al., ex-
plore a set of insulin derivatives that possess a short cross-
link across two of the three native amines as a means to ex-
plore the relationship of molecular constraint to in vitro bio-
activity. They demonstrate a negative impact on bioactivity
from constraining the insulin structure; however, these
unique new insulin analogues may contribute to the future
development of prodrugs that might be chemically or enzy-
matically activated to achieve a more precise PK profile
leading to enhanced insulin pharmacodynamics.
(a)
O
N NH
NH
O CH3
N B
HO OH
(b)
H3C O O
H3C
N
NH
O O
(c) H3C CH3
O
NH
N
H3C NH NH O O
O
H3C
CH3 O
H3C CH3
CH3
Figure 2. Non-peptide features in selected examples taken from
Table 2: (a) bortezomib, (b) enalapril, (c) boceprevir.
Examples of other therapeutic peptides prepared via
chemical synthesis that have reached major pharmaceutical
markets can be found in Table 2 [25, 26]. It is worth noting
that several of these molecules have non-peptide features,
such as the boronic acid in bortezomib and the phenethyl
sidechain in enalapril, as well as the more extensive cyclic
and other modifications in boceprevir, as shown in Figure 2.
Interestingly, of the synthetic marketed peptide-based
drugs listed in Table 2, six of them—captopril, tirofiban,
epifibatide, bivalirudin, ziconotide, and exenatide—are de-
rived from animal venoms. These drugs and their analogues
or competitors range in size from three to 44 amino acids in
Angell et al.
length and act as ACE inhibitors, platelet inhibitors/ antico-
agulants, ion channel blockers, and incretin receptor antago-
nists (e.g., glucagon-like peptide (GLP-1)) [27]. The success
of antidiabetic GLP-1 compounds has led to intense competi-
tion in that space, with at one point in time, perhaps two
dozen or more companies competing head to head. Similarly,
the success of analgesic peptide ziconotide (Prialt®) from
venomous cone snail, Conus magus, identified an alternative
molecular target for treating pain (N-type calcium channels)
and has revitalized the quest to find non-addictive, non-
opioid painkillers using peptide therapeutics [28, 29]. The
article by Napolitano and Holford in this Special Issue re-
views the latest progress in identifying and screening for
bioactive venom peptides in order to increase access to this
enormous reservoir of peptide compounds with biomedical
and therapeutic applications that are revealing new targets
for pharmaceutical development (Figure 3).
9(120PEPTIDE DRUG',6&29(5<
CH3
Litoria aurea Conus magus Naja atra
ANTIMICROBIAL MODIFIED PEPTIDIC ANTICANCER
PEPTIDES DRUGS PEPTIDES
OH Aurein Ziconotide Bestatin
NH2
Figure 3. Venom Peptide Drug Discovery. Drug discovery and
development from venomous animals have produced breakthrough
antimicrobial (aurein), analgesic (ziconotide), and anticancer (bes-
tatin) drugs. While these drugs have provided novel targets, major
hurdles such as making peptide therapeutics orally active for deliv-
ery via pills is a barrier for the future development of venom-
derived drugs.
Other peptide products that have gained approval for
marketing in recent years cover a wide range of indications,
mechanisms, and targets, including drugs that act as a surfac-
tant, a protease inhibitor, or a ligand for Erythropoietin
(EPO), somatostatin, guanylate cyclase, or GLP-2. Again,
some of these so-called peptides are modified in material
ways, such as the anticancer protease inhibitor, carfilzomib,
with novel epoxide and morpholine residues, and the anti-
Building on Success: A Bright Future for Peptide Therapeutics Protein & Peptide Letters, 2018, Vol. 25, No. 12 1047

Table 2. A sampling of synthetic therapeutic peptides that have reached major pharmaceutical markets.

Class of Drug Examples Length (aa)

ACTH corticorelin, cosyntropin, seractide 24-41

ACE inhibitors captopril, enalapril, lisinopril 3

Angiomax bivalirudin 20

ARBs saralasin 8

Antidiabetics exenatide, liraglutide, pramlintide 31-39

Anti-HIV boceprivir, enfuvirtide 3-36

Calcitonins salmon calcitonin 32

Cardiovascular eptifibatide 7

CCK ceruletide 8-10

CNS ziconotide 2-25

GHRH somatorelin 44

GnRH agonists goserelin, leuprolide 9-10

GnRH antagonists aberelix 10

Oxytocin atosiban 7

Secretin porcine secretin 27

Somatostatin octreotide 7

Aggrastat tirofiban ~3

Vasopressin desmopressin 8

Miscellaneous bortezomib, glatiramer, teduglutide 2-33

Recombinant expression or fermentation nesiritide, vancomycin 7-32

(Abbreviations: aa, amino acids. ACTH, adrenocorticotropic hormone. ACE, angiotensin converting enzyme. ARB, angiotensin receptor blocker. HIV, human immunodeficiency
virus. CCK, cholecystokinin. CNS, central nervous system. GHRH, growth hormone releasing hormone. GnRH, gonadotropin releasing hormone).

bacterial agent, oritavancin, with a chloro-biphenyl moiety
(Figure 4) [30].
Antimicrobial and anticancer peptides have garnered
much attention over the years. Sometimes these agents are
used essentially as is, but at other times amino acid substitu-
tion, structural fusion, or conjugation with chemotherapeu-
tics may be required to achieve the desired efficacy [31]. The
manuscript by Casciaro and Mangoni in this Special Issue
describes the activity of two antimicrobial peptides: escu-
lentin-(1-21) and an analogue with the Leu14 and Ser17
residues inverted to D-isomers (esculentin-(1-21)-1c). The
researchers show in a series of assays that these esculentins
possess anti-microbial activity against P. aeruginosa, a bac-
terial strain that colonizes the lungs of cystic fibrosis pa-
tients. The authors show that both peptides exert bactericidal
activity against a biofilm form of the above strain, impor-
tantly without inducing resistance, which is commonly seen
in the course of treatment with ciprofloxacin, tobramycin,
and other more conventional antibiotics. Additionally, syn-
ergistic activity is shown when using Esc-(1-21) and Esc-(1-
21)-1c in the presence of the antibiotic aztreonam. Various
anticancer mechanisms have been explored through peptide-
based approaches, as outlined in Table 3.
Before concluding this overview, let’s discuss intellectual
property and the worldwide peptide market ever so briefly.
The number of patent applications on peptide pharmaceuti-
cals has dropped from an all-time high in the early 2000s,
but such a drop is also evident with non-peptide drugs. The
worldwide market for peptide drugs has exceeded $10 billion
per year since ~2010, with the old standbys, goserelin,
leuprolide, and octreotide totaling a quarter of the peptide
market in 2011 [32].
Given the above, what are the best targets and therapeutic
areas today for new peptide drugs? From a chemical perspec-
tive, researchers might decide to:
• Avoid crowded areas, well-exemplified by GLP-1 anti-
diabetics as well as certain immuno-oncology targets.
• Focus on peptides smaller than 40-50 amino acids (and
maybe smaller still).
• Consider employing backbone and/or sidechain modifi-
cations to increase the stability of the synthesized pep-
tides, enhance their activity, and/or underpin essential
patentable novelty (e.g., N-substituted glycines [33] or
moieties that will react covalently [34]); i.e., neither
1048 Protein & Peptide Letters, 2018, Vol. 25, No. 12 Angell et al.

Cl

OH
NH CH3

H3C
O
OH
O OH
O O O O OH
CH3
N NH NH O Cl O O Cl
NH NH H3C
O O
O CH3 O CH3 O
HO O OH
O O
CH3 CH3 H2N O
H
N
H
N NH
CH3 N NH CH3
NH
H O
HO HN O H2N O CH3

O O CH3

OH
HO OH

Figure 4. Non-peptide features in additional examples of approved peptide therapeutics: (a) carfilzomib, (b) oritavancin.
Table 3. Mechanisms of anticancer peptides.

Mechanisms Actions Targets Examples

Tumor angiogenesis Inhibition Growth factors Ang, EGF, FGF, PDGF, PLGF, TNF, VEGF

Tumor apoptosis Induction Cationic peptides, death receptor signaling Lactoferricin, NF-κB

Tumor necrosis Induction Mitochondria, membrane disruption Kahalalide

Immune system Modulation Interferon pathways Bestatin, FK-565, muramyl peptides

Kinases and proteases Inhibition Erk, FGF, MAPK, MMPs, PKB FGF8b-13

Functional proteins Interference Matrix oncoproteins, transcription factors Int-H1-S6A, F8A, BACl-ELP-H1
(Abbreviations: Ang, angiogenin. EGF, epidermal GF. ELP, elastin-like peptide. Erk, extracellular signal-related kinase. FGF, fibroblast GF. GF, growth factor. MAPK, mitogen-
activated protein kinase. MMP, matrix metalloprotease. NF, nuclear factor. PDGF, platelet-derived GF. PKB/Akt, protein kinase B. PLGF, placental GF. TNF, tumor necrosis factor
(i.e., TNFα). VEGF, vascular endothelial GF).

unmodified nor traditional simple peptide modifications,
such as D/L amino acid substitution, may be sufficient.
However, it is essential to consider the potential effect
on final cost of goods when making peptide modifica-
tions.
• Increase efforts to use computational methods to model
peptide ligand:receptor interactions. Synthesizing pep-
tides is costly and labor intensive, however, developing
in silico methods to screen peptide mutants narrows the
funnel to highlight potential hits, while significantly re-
ducing experimental costs. Recent efforts have demon-
strated this approach successfully when applied to find-
ing a more selective α-GID snail venom peptide for the
α4β2 nicotinic receptor, which is widely expressed in
the brain and a validated target for smoking cessation
[35].
Possible strategies to identify novel peptide therapies
include the following (in no particular order):
• Functional/phenotypic assays (e.g., mitochondrial per-
meability transition): looking at cellular physiology at a
whole-cell or organellar level, not at specific molecular
targets. The applicable molecular targets might be iden-
tified later if this path is taken. Mitochondrial dysfunc-
tion underlies some rare genetic diseases as well as a
large number of age-related chronic diseases. Given that
80% of adults over 65 years of age have at least one
chronic condition, while 68% have two or more chronic
conditions, age-related diseases represent an increas-
ingly important area of focus today. In addition, the arti-
cle in this Special Issue by Szeto on stealth peptides that
target rare genetic diseases involving mitochondrial dys-
function demonstrates how aromatic-cationic peptides,
such as elamipretide, provide a novel paradigm for the
treatment of multiple chronic diseases.
• Multidrug resistance blockade (e.g., P-glycoprotein
(PGP) and related transporters): making old drugs more
effective.
• Matrix Metalloprotease (MMP) inhibitors: but only if
lessons can be learned from past failures to point to a
more productive direction.
• Dual mechanism compounds: for example, novel pep-
tides that block two growth factor pathways simultane-
ously. Or novel immunomodulatory peptides designed
to hit two targets simultaneously (e.g., PD-1 and PD-L1,
protein death ligands that are checkpoint inhibitors, cur-
rently of great interest in immuno-oncology). A poten-
Building on Success: A Bright Future for Peptide Therapeutics
tial resource for identifying dual mechanism compounds
is animal venoms, which are a complex mixture of 10-
200+ peptides working in a concerted manner to modu-
late physiological function. Often referred to as ‘cabals’,
the concentrated actions of animal venoms on molecular
targets are extremely potent and precise.
• Kinases: specifically, those cancer targets where small
molecule non-peptides have not been effective, or where
features commonly associated with peptides as liabilities
(e.g., short duration of action) are actually a strength.
• Non-GLP GPCRs: for example, those of interest in
metabolic disorders, including diabetes [36]. The article
in this Special Issue by Naider and Anglister describes
how homogeneously sulfated peptide surrogates for the
N-terminus of CCR5, and many other chemokine recep-
tors, are proving very useful in elucidating both the
structure-function relationships of the receptor and the
3-dimensional structure of the receptor bound to cognate
ligands.
• Opiates devoid of classical side effects: for example,
new peptide opiate analogues lacking typical undesired
adverse effects based on very recent discoveries [37].
The review article in this Special Issue by Singh and
Srivastava describes novel, multi-functional peptide hy-
brid compounds combining opioid receptor agonism
with activity at other pain modulating receptors to ad-
dress the challenges associated with neuropathic pain
and opioids. These peptide hybrid compounds offer an
attractive solution to reduce or eliminate opiate-related
side effects. The authors also describe novel advances in
peptide engineering of chimeric and hybrid peptides tar-
geting several other therapeutic areas where the de-
signed peptide constructs provide peptides that surpass
native peptides in efficacy, specificity, and resistance to
enzymatic degradation.
• Conformational dynamics: peptides that stabilize or
convert undesired conformations of key proteins, such
as apolipoproteins or prions, of interest in cardiovascular
and neurodegenerative diseases.
• Protein-protein interactions: many to date ‘undruggable’
target proteins are important in various disease states.
These proteins are considered undruggable because they
lack a cavity for small molecule inhibitors to bind, and
they interact with their protein partners through exten-
sive and flat surfaces. Peptide drugs can offer improved
potency, specificity, and selectivity in these settings.
The peptide is usually based on the sequence of the
binding region between the two proteins. The linear se-
quences might originate from a loop or helix within a
structured domain, or from a disordered region in pro-
tein termini or between defined domains [38].
CONCLUSION
As others have noted, therapeutic peptides have recently
undergone a ‘renaissance’ and will continue to improve their
ranking as viable drugs [39]. Peptides are quite versatile and
can be applied to a broad range of indications. With many
novel approaches to peptide hit generation, peptide modifica-
Protein & Peptide Letters, 2018, Vol. 25, No. 12 1049
tion for cell permeability, conjugation for half-life extension,
and ongoing advances in drug delivery technologies, the
future is bright for the discovery and development of peptide
therapeutics. It is interesting to note that, for the first dozen
years of the 21st century (2000-2012), half of all approved
peptide drugs were linear peptides, though increasingly
novel structures including macrocycles are making signifi-
cant headway through research and into development. Thus,
new discoveries provide opportunities for the advancement
of linear peptides as well as extensively modified peptides
(e.g., unnatural amino acid and backbone modified peptides,
macrocyclic and lariat or lasso peptides [40, 41], and stapled
peptides [42]). Some of the latest macrocyclic pep-
tide/peptoid hybrids have been successfully designed to be
cell-permeable and even orally bioavailable [43]. Addition-
ally, the increasing rate of discovery of venom peptides
opens another route for novel peptide drug research and de-
velopment [44]. All told, there is little doubt that peptide
research will continue to adapt to the latest therapeutic
needs, improving and saving the lives of those who are in
greatest need of breakthroughs in medicine in 2020 and be-
yond.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
Yvonne Angell is an employee of ChemPartner and has
no conflict of interest. Mandë Holford is a professor in
Chemistry at CUNY with scientific appointments at The
American Museum of Natural History and Weill Cornell
Medicine and has no conflict of interest. Walter H. Moos
consults with and/or serves on the boards of various biotech-
nology, pharmaceutical, and related companies from time to
time, where he may receive compensation including stock
options, and he receives compensation from ShangPharma
Innovation, Inc., a healthcare venture capital firm.
ACKNOWLEDGEMENTS
All authors contributed substantially to researching and
writing this article.
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