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REVIEWS
Pseudomonas aeruginosa infections in cyclophosphamidetreated (neutropenic) mice, it exhibits haemolytic activity
at higher concentrations, and a protegrin derivative
IB367 (iseganan) failed in PhaseIII clinical trials of
oral mucositis2931.
Most of the natural cationic peptides are much less
(~10100fold) active than these AMPs and are strongly
antagonized by physiological concentrations of monoand divalent cations as well as polyanionic polymers
like glycosaminoglycans and mucin32. Thus, new design
approaches are required that enable the identification of
more cost-effective sequences (that is, smaller sequences
without post-translational modifications) that are highly
active, have broad-spectrum activity without associ
ated toxicities, good pharmacokinetics and a desired
selectivityprofile.
Cyclophosphamide-treated
(neutropenic) mice
Animals lacking neutrophil
granulocytes. Neutrophils
represent a primary defence
against bacterial infections,
partially through phagocytosis
and neutrophil extracellular
traps containing high
local concentrations of
antibacterial agents.
Chemogenomics
A drug discovery approach
that uses high-throughput
technology to study the
genomic effect of chemical
compounds on target families,
thereby complementing
disease area- and singletarget-oriented concepts.
Kernel methods
A class of algorithms for
computational pattern analysis.
Kernel functions allow
the detection of nonlinear
relationships among data
without having to fit a nonlinear
model (known as a Kernel trick).
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REVIEWS
a
AMP
Outer leaet
Inner leaet
50 nanoseconds
100 nanoseconds
REVIEWS
Markov models69,70. Recently, feature-extraction methods
AMP databases
As natural AMPs are largely derived from gene-coded
sequences, bioinformatics methods have been applied to
create databases of known AMPs as well as tools to specif
ically predict AMPs from genomes that have not yet been
annotated. For example, the AMPer resource was devel
oped with the aim of classifying natural AMPs, as well as
predicting novel AMPs in the bovine genome using hidden
Synthetic AMPs
To develop AMPs into therapeutics, several objectives
must be met. As an anti-infective treatment, an AMP
must be active against the pathogen of interest and have
low toxicity at the therapeutic dose (that is, it must have a
high therapeutic index). Recent research on AMPs has
focused on methods to search through the constella
tion of known or predicted peptide sequences either
empirically or computationally for peptides with
desired properties, and these approaches are continually
evolving. We distinguish three research approaches:
modification of known AMP sequences (known as
templates) with limited computational input; rigorous
biophysical modelling to understand peptide activity;
and virtual screening. We outline these methodologies and
data requirementsbelow.
Template-based studies. Studies of AMP activity based
on a template AMP with known activity seek to identify
peptides with greater antimicrobial activity or reduced
toxicity based on altered amino-acid sequences84. These
studies have often systematically but incompletely
changed a single amino acid in the peptide to identify
amino acids and positions that are important for activity.
Cecropin, magainin, protegrin and lactoferricin have all
been used as AMP templates. In most cases, the source of
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REVIEWS
Molecular dynamics
Simulations that compute
conformations and physical
movements of molecules over
a simulated period of time.
Physically motivated force
fields in different surroundings
(for example, in a vacuum or
water box) are often used to
compute interaction energies
between particles.
REVIEWS
Start
Seed peptide
(or peptides)
De novo
Optimized peptide
End
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REVIEWS
Table 1 | Selection of computer-based peptide design concepts and approaches
Year
Fitness function
Design strategy
Description
Refs
1994
(and 1998)
Artificial neural
network
Evolutionary
algorithm
92,187,
201,202
2004
Fold stability,
energy-based
probabilities
Amino-acid
replacement
203
2005
(and 2006)
Docking
simulation
Evolutionary
algorithm,
heuristic
204,205
2006
Regular
grammar
Linguistic
model
93
2007
206
2007
Experimentally
optimized
alignment matrix
207
2007
Artificial neural
network
Ant colony
optimization
algorithm
208
2008
Hidden Markov
model (HMM)
2008
Molecular
dynamics
simulation
Evolutionary
algorithm
2009
Artificial neural
network
2011
Artificial neural
network
Genetic
algorithm
70
209
149,150
151
REVIEWS
Box 1 | Principles of adaptive peptide design
Evolutionary algorithms are based on the iterative generation of potential solutions
(xi) to a problem and the selection of the best solution according to a (usually)
multimodal fitness function, defined as f(xi)186. In peptide design, the underlying
fitness landscape is either provided by a determination of the candidate peptides
using actual biochemical activity, or by computing a structureactivity landscape.
The ideal measure of fitness is an experimental response. If sufficient training data
are available, f(xi) can be expressed by a machine-learning model187. To find the best
solution in the fitness landscape containing An peptides (where A is the number of
different building blocks, and n is the peptide length), the population of solutions
(peptides) must be able to adapt to the local ruggedness of the landscape so that
the search does not prematurely converge in areas of low fitness. Such a desired
behaviour can be achieved using so-called strategy parameters that is, variables
that capture the progress made within a population and are used for projecting a
promising search path for the next generation.
A straightforward way to perform an informed search is illustrated in the figure. A simple
evolution strategy188 was implemented to find the global optimum in a virtual fitness
landscape. For clarity, in this case a mathematical function serves as the fitness
estimator f(xi) and is a substitute for an experimental activity assay. For each of the
50 simulated generations, ten offspring (x1 to x10) were bred from a single parent
(indicated by the arrow, xP, as shown in the left panel of the figure). Their spread
around the location of the parent approximates a normal distribution with width
(known as step size), which serves as the adaptive strategy parameter in this
algorithm. This factor is a property of the current parent that is, the best among the
set of offspring solutions, x, from the previous generation. In every new generation,
a new population (x) will be created so that its position in the search space satisfies
a localized distribution with width and center xP. As only the best solution (and its
associated individual value) is picked as the next parent in the subsequent selection
step, over time small values of will evolve in rugged parts of the fitness landscape or
near an optimum point (leading to small steps in the search space), whereas large
values of will dominate in flat, plateau-like areas (leading to large steps in the search
space). It is important to realize that adapts to the local form of the fitness landscape
so that optimal progress of the search takes place, without any predefined cooling
schedule, operator intervention or external control.
Different implementations of evolutionary optimization use different mechanisms
for adaptation189,190, and the adaptive step-size concept presented here is a
characteristic of evolution strategies, which in the case of peptide design
work directly on molecular properties such as residue polarity, side-chain volume,
hydrophobic moment, and so on. By contrast, genetic algorithms first code molecular
properties in the form of bitstrings representing a peptides genotype, and then apply
mutation and recombination operations to the bitstrings to generate offspring191.
The figure provides an example of evolutionary optimization. A mathematical
function (indicated by the contour plot on the left) served as a fitness function that
had to be optimized by an evolution strategy. The size of the population was 10
individuals (search agents), and a single parent (elitism) was selected in each of
the 20 simulated generations. After 10 generations the search converged close to
the global optimum (as indicated by the trend line joining the grey points below).
Note that the distribution of the population is adaptive (step size, , represented
as the blue curve on the right). In terms of molecular design, the value corresponds
to compound diversity.
End
Start
Fitness
10th
generation
10th generation
End
Step size
Start
Generation
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Hydrophobic moment
The hydrophobicity of
a peptide measured for
different angles of rotation
per residue.
Signal peptides
Typically aminoterminal
stretches of amino-acid
residues that are required for
the targeting of proteins to
their intra- and extracellular
destination.
KVRRYNRRR
IYIIIWRTK
HYKFQRWIK
RQMRSIRGR
KYKQRVQHI
(5.88)
(4.39)
(3.10)
(2.37)
(1.57)
WRWWKIWKR
RWRRWKWWL
WKKWWKRRW
KRRMRWIIM
KWRFKWWKR
(0.06)
(0.14)
(0.17)
(0.79)
(0.82)
Relative IC50
ate
din
or
Co
Coordinate 1
REVIEWS
Table 2 | Selected host defence peptides in drug development
Name
Sequence
Company
Description
Application
Trial
phase
Comments
Clinical trial
identifiers
and further
information
Pexiganan
acetate
(MSI 78)
GIGKFLKK
AKKFGKAF
VKILKK
MacroChem
Synthetic
analogue of
magainin2 derived
from
frog skin
Topical antibiotic
III
No advantage
demonstrated over
existing therapies
NCT00563433
and
NCT00563394
Omiganan
(MX226/
MBI226)
ILRWPW
WPWRRK
Migenix/
BioWest
therapeutics
Synthetic cationic
peptide derived
from indolicidin
NCT00027248
and
NCT00231153
Omiganan
(CLS001)
ILRWPW
WPWRRK
Cutanea Life
Sciences/
Migenix
Synthetic cationic
peptide derived
from indolicidin
Severe acne
and rosacea;
anti-inflammatory
II/III
Significant efficacy
in PhaseII trials for
both indications;
in PhaseIII trials
NCT00608959
Iseganan
(IB367)
RGGLCY
CRGRFC
VCVGR
Ardea
Biosciences
Synthetic 17-mer
peptide derived
from protegrin1
Oral mucositis
in patients
undergoing
radiation therapy
III
No advantage
demonstrated over
existing therapies
NCT00022373
hLF111
GRRRRS
VQWCA
AM-Pharma
Cationic peptide
fragment
comprising
amino-terminal
amino acids
111 of human
lactoferricin
Bacteraemia and
fungal infections
in immunocompromised
haematopoetic
stem cell
transplant
recipients
I/II
Significant efficacy
observed in PhaseI
trials; mechanism
of action appears to be
immunomodulatory
rather than antibiotic;
PhaseII trials
initiated after a
long delay
NCT00509938
XOMA629
KLFR-(dnaphtho
-Ala)-QAK(d-naphtho
-Ala)
Xoma
Derivative of
bactericidal
permeabilityincreasing
protein
Impetigo
IIa
No PhaseIIa results
available (trial started
in July 2008)
XOMA website
PAC-113
AKRHHG
YKRKFH
Pacgen
Biopharma
ceuticals
Synthetic 12-mer
peptide derived
from histatin3
and histatin5
Oral candidiasis
IIb
PhaseIIb results
(announced June 2008):
34% increase in
primary end point
efficacy level; PhaseIII
trial not initiated
NCT00659971
CZEN002
(CKPV)2
Zengen
Dimeric octamer
derived from
melanocytestimulating
hormone
Vulvovaginal
candidiasis;
anti-inflammatory
IIb
Positive efficacy
results announced;
PhaseIIb trial is
a dose-ranging
study
US Patent
application
serial number
09/535066
IMX942
KSRIVPA
IPVSLL
Inimex
Synthetic cationic
peptide derived
from IDR1 and
bactenecin
Nosocomial
infection, febrile
neutropenia
Ia
Inimex
Pharmaceuticals
website
OP145
IGKEFK
RIVERIK
RFLREL
VRPLR
OctoPlus;
Leiden
University,
The
Netherlands
Synthetic
24-mer peptide
derived from
LL-37 for binding
to lipopoly
saccharides or
lipoteichoic acid
Chronic bacterial
middle ear
infection
II (completed)
Clinical proof-of-efficacy
in PhaseII trials;
no PhaseIII trials
proposed yet
ISRCTN84220089
Ghrelin210
GSSFLSPE
HQRVQQ
RKESKKPP
AKLQPR
University
of Miyazaki,
Japan;
Papworth
Hospital,
Cambridge, UK
Endogenous
host-defence
peptide
Airway
II
inflammation,
chronic respiratory
infection and
cystic fibrosis
JPRNUMIN000002599,
JPRNUMIN000001598
and
NCT00763477
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REVIEWS
Table 2 (cont.) | Selected host defence peptides in drug development
Name
Sequence
Company
Description
Application
Trial
phase
Comments
Clinical trial
identifiers
and further
information
PMX30063
Structure
not
disclosed
PolyMedix
Arylamide
oligomer mimetic
of a defensin
Acute bacterial
skin infections
caused by
Staphylococcus
spp.
II
NCT01211470;
PolyMedix
website
Delmitide
(RDP58)211
RXXXRX
XXGY
(X=
norleucine)
Genzyme
Semisynthetic
damino acid
decapeptide
derived from HLA
class I B2702
Inflammatory
bowel disease
II (completed)
A protease-resistant,
d-amino acid-containing
peptide with similar
efficacy to asacol;
attempting to
improve activity
through formulation
Genzyme
website;
ISRCTN84220089
Plectasin212
GFGC1NG
PWDEDD
MQC2HNH
C3KSIKGYK
GGYC1AKG
GFVC2KC3Y)
Novozymes
Fungal defensin;
candidate in
development is
an amino-acid
substitiution
variant
Bacterial
diseases
Preclinical
Excellent efficacy
demonstrated in
animal models
Novozymes
website
HB1345
DecanoylKFKWPW
Helix BioMedix
Synthetic
lipohexapeptide
Acne;
broad-spectrum
antibiotic
Preclinical
Looks promising as
this is a very small
lipopeptide
Helix BioMedix
website
HLA, human leukocyte antigen; IDR1, innate defence regulator1; LL-37, human cathelicidin antimicrobial peptide LL-37.
REVIEWS
Deep-ultraviolet resonance
Raman spectroscopy
A biophysical technique for
sensitive secondary-structure
detection in peptides and
proteins, and for confident
discrimination between
secondary structure types.
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Acknowledgements
R.E.W.H. holds a Canada Research Chair position, and his current peptide research is supported by the Canadian Institutes
of Health Research (CIHR). C.D.F. holds a CIHR postdoctoral
fellowship. This study was partially supported by grants to
J.A.H. and G.S. from the Swiss National Science Foundation
(Grant number: 205321134783) and the German Research
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FURTHER INFORMATION
Robert E. W. Hancocks homepage:
http://www.cmdr.ubc.ca/bobh
Gisbert Schneiders homepage: http://www.modlab.ethz.ch
AMPer A Database And An Automated Discovery Tool
For Gene-Encoded Antimicrobial Peptides:
http://marray.cmdr.ubc.ca/cgi-bin/amp.pl
The Antimicrobial Sequences Database:
http://www.bbcm.univ.trieste.it/~tossi/amsdb.html
The Antimicrobial Peptide Database and Analysis System:
http://aps.unmc.edu/AP/main.html
BACTIBASE Database: http://bactibase.pfba-lab-tun.org
CAMP Collection of Antimicrobial Peptides:
http://www.bicnirrh.res.in/antimicrobial
ClinicalTrials.gov website: http://clinicaltrials.gov
COPE Cytokines & Cells Online Pathfinder Encyclopedia:
http://www.copewithcytokines.org
DEFENSINS Knowledgebase: http://defensins.bii.a-star.edu.sg
Genzyme website RDP58 (delmitide) partnering
overview: http://www.genzyme.com/corp/licensing/RDP58_
Non-Confidential_Overview_01Mar2007.pdf
Helix BioMedix website (anti-infective program):
http://helixbiomedix.com/antiinfective.html
Inimex Pharmaceuticals website:
http://www.inimexpharma.com/prod_tech_profile.html
Novozymes website (27 May 2010 press release):
http://www.novozymes.com/en/news/news-archive/
Pages/45873.aspx
PenBase: http://penbase.immunaqua.com
Peptaibol Database:
http://peptaibol.cryst.bbk.ac.uk/home.shtml
PhytAMP A database dedicated to plant antimicrobial
peptides: http://phytamp.pfba-lab-tun.org
PolyMedix website PMX-30063 Antibiotic Factsheet:
http://www.polymedix.com/pdf/PMX-30063factsheet.pdf
Recombinantly Produced Antimicrobial Peptides Database:
http://faculty.ist.unomaha.edu/chen/rapd
XOMA website (24 July 2008 press release):
http://www.xoma.com/company/news-events/pressreleases/index.cfm?releaseID=324334
ALL LINKS ARE ACTIVE IN THE ONLINE PDF