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 .
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP001

Amino Acids, Peptides and Proteins

Volume 42
 .
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP001 View Online
 View Online

A Specialist Periodical Report

Amino Acids, Peptides

and Proteins
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP001

Volume 42

Editors
Maxim Ryadnov, National Physical Laboratory, London, UK
Ferenc Hudecz, Eötvös Lorand University, Budapest, Hungary

Authors
Kenichi Akaji, Kyoto Pharmaceutical University, Japan
Zoltán Bánóczi, Eötvös L. University, Hungary
Annarita Falanga, University of Naples Federico II, Italy
Stefania Galdiero, University of Naples Federico II, Italy
Ferenc Hudecz, Eötvös L. University, Hungary
Pirjo Laakkonen, University of Helsinki, Finland
Vadim Le Joncour, University of Helsinki, Finland
Marc-Philipp Pfeil, University of Oxford, UK, and Harvard Medical School, USA
János Szolomájer, University of Szeged, Hungary
.

Anthony Watts, University of Oxford, UK

Márta Zarándi, University of Szeged, Hungary
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP001 View Online

ISBN: 978-1-78801-002-3
PDF eISBN: 978-1-78801-062-7
EPUB ISBN: 978-1-78801-408-3
ISSN: 1361-5904
DOI: 10.1039/9781788010627

A catalogue record for this book is available from the British Library

r The Royal Society of Chemistry 2018

All rights reserved

Apart from fair dealing for the purposes of research for non-commercial
purposes or for private study, criticism or review, as permitted under the
.

Copyright, Designs and Patents Act 1988 and the Copyright and Related
Rights Regulations 2003, this publication may not be reproduced, stored or
transmitted, in any form or by any means, without the prior permission in
writing of The Royal Society of Chemistry, or in the case of reproduction
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by the appropriate Reproduction Rights Organization outside the UK.
Enquiries concerning reproduction outside the terms stated here should
be sent to The Royal Society of Chemistry at the address printed
on this page.

Published by The Royal Society of Chemistry,

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Registered Charity Number 207890

For further information see our web site at www.rsc.org

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CR0 4YY, UK
 Preface
DOI: 10.1039/9781788010627-FP005

Since 1969 this series of specialist periodical reports has covered the area
of protein and peptide science without favouring topical polularity. This
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP005

approach has helped to keep abreast with achievements in seemingly less

acknowledged areas that would have limited coverage in the mainstream
scientific literature. As any other series of this type these reports are
presented as research accounts that evolve owing to emerging research
areas. This volume continues the tradition of bringing new and estab-
lished science together. The book reviewes literature predominantly
published over the last three years, with each chapter providing funda-
mental concepts and terminology.
This 42nd volume opens with a detailed discussion of contemporary
developments in the applied research of amino acids (Zarandi and
Szolomajer). The review focuses on the chemistry, origin and physical
properties of amino acids. It starts with naturally occuring derivatives,
both L- and D-epimers, introducing fundamentals of structural diversity,
which is logically followed by application highlights ranging from
pharmaceuticals to food supplements. Mechanisms of biological action
and biosynthetic routes towards particular derivatives are then described,
bridging with chemical syntheses and low- and high-resolution analytical
methods used for physico-chemical characterisation. The second chapter
ramps up the discussion to the challenge of synthetic strategies for the
bioconjugation of amino acids and peptides (Banoczi and Hudecz).
Various bioconjugates are discussed as proven research tools and valid-
.

ated precursors for therapeutic agents. The chapter predominantly

stresses the importance of synthetic and semi-synthetic approaches,
explaining conjugation mechanisms and presenting linkers commonly
used for ligation and labelling. Therapeutic agents are exemplified by
conjugates with known biologically active peptide moieties including
the cell-adhesion RGD motif and antimicrobial peptides. Selected areas
of applications feature peptide conjugates as immunogens and cell-
penetrating drug delivery systems. Mechanisms by which peptides
interact with, cross or disrupt cellular membranes are given in the fol-
lowing chapter (Pfeil and Watts). This report tackles the challenge of
elucidating inter- and intra-molecular interactions underpinning the
biological function of antimicrobial peptides, synthetic and native. State-
of-the-art NMR and EPR methods and innovative approaches are detailed
with regards to solving lipid-peptide ensembles in membrane bilayers.
The chapter links the conserved physicochemical parameters that are
characteristic of antimicrobial peptides with the physical basis of their
biological action. Structure-activity relationships of naturally occuring
antimicrobial peptides are discussed in the following chapter (Falanga
and Galdiero), which relates to the preceding report with an attempt to
find a generic rationale for developing such peptides as drugs. The
chapter gives a contemporary overview of recent and on-going efforts to

Amino Acids, Pept. Proteins, 2018, 42, v–vi | v

c The Royal Society of Chemistry 2018
 View Online

commercialise antimicrobial peptides with specific references to drug

developers active in the area. Pharmaceutical developments addressing
the problem of infectious diseases are further discussed in the next
chapter (Akaji), which reviews progress in the design of selective peptide-
based ligands able to interact with 3C like proteases of coronaviruses.
The chapter is written in a form of an R&D protocol that provides
information as to the structure of the protein target, its function in vir-
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP005

uses and mechanisms of its inhibition by a variety of peptidomimetics.

Comparative efficacies of the peptidomimetics presented are tabulated
into IC50 values obtained against coronoviruses causing Severe Acute and
Middle East Respiratory Syndromes (SARS and MERS, respectively). The
chapter is built around the traditional concept of ligand–protein target-
ing, which remains key for pharmaceutical industry. A complementary
strategy is presented in the closing chapter of the volume (Le Joncour and
Laakkonen), which drives the topic of peptide-based drugs to exploiting
the intrinsic properties of the peptides to specifically target cancer cells.
Screening combinatorial technologies, e.g. phage displays, are discussed
as effective discovery platforms for novel and highly selective peptides
targeting tumour cells. The chapter outlines pros and cons of ex vivo,
in vivo and in vitro screening approaches, highlighting technical issues
that are critical for further progress. The chapter then concentrates on
identified peptides with known and unknown targets and the application
of these peptides for both tumour imaging and therapy. The report
concludes the volume with a neat analogy of a Swiss-Army Knife relating
to the multi-purpose function of peptides.

Maxim Ryadnov and Ferenc Hudecz

.

vi | Amino Acids, Pept. Proteins, 2018, 42, v–vi

 CONTENTS

Cover
Front cover image courtesy of Michael Shaw
and Angelo Bella. The image shows a
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP007

colour-coded depth projection of

self-assembled peptide fibres arranged into
star-like structures.

Preface v

Amino acids: chemistry, diversity and physical properties 1

Márta Zarándi and János Szolomájer
.

1 Naturally occurring amino acids 1

2 Chemical synthesis and resolution of amino acids 12
3 Analytical methods 51
Abbreviations 66
References 67

Amino acid and peptide bioconjugates 85

Zoltán Bánóczi and Ferenc Hudecz

1 Introduction 85
2 Synthesis 85
3 Selected applications of peptide-bioconjugates 112
Abbreviations 129
Acknowledgements 131
References 131

Amino Acids, Pept. Proteins, 2018, 42, vii–ix | vii

c The Royal Society of Chemistry 2018
 View Online

Magnetic resonance studies of antimicrobial 146

peptides in membranes
Marc-Philipp Pfeil and Anthony Watts

1 Introduction: peptide–lipid interactions 146

2 Electron paramagnetic resonance (EPR) 152
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP007

3 Solid-state nuclear magnetic resonance (NMR) 166

4 Discussion 179
Acknowledgements 181
References 181

Emerging therapeutic agents on the basis of naturally occurring 190

antimicrobial peptides
A. Falanga and S. Galdiero

1 Introduction 190
2 AMPs origin and classification 193
3 Mechanism of action 195
4 SAR of AMPs 199
5 Design of novel AMPS with improved activity 203
6 Nano-Antimicrobials: delivery systems for AMPs 208
7 AMPs with other activities 211
8 AMPs in clinical applications 212
.

9 Conclusion 218
References 219

Advances in the design of ligands interacting with 228

3CL protease of novel coronaviruses causing infectious
respiratory syndrome
Kenichi Akaji

1 Introduction 228
2 Coronavirus 3CL protease 230
3 Inhibitors of 3CL protease 238
4 Conclusions 274
References 275

viii | Amino Acids, Pept. Proteins, 2018, 42, vii–ix

 View Online

Targeting peptides, a Swiss-Army Knife against cancer 280

Vadim Le Joncour and Pirjo Laakkonen

1 Introduction 280
2 The phage display technology: screening and 281
characterisation of tumour targeting peptides
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP007

3 Targeting peptides for cancer imaging and therapy 292

4 Concluding remarks 307
List of abbreviations 307
References 309
.

Amino Acids, Pept. Proteins, 2018, 42, vii–ix | ix

 A short guide to abbreviations and
their use in peptide science
Abbreviations, acronyms and symbolic representations are very
much part of the language of peptide science – in conversational
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP010

communication as much as in its literature. They are not only a

convenience, either – they enable the necessary but distracting
complexities of long chemical names and technical terms to be pushed
into the background so the wood can be seen among the trees. Many of
the abbreviations in use are so much in currency that they need no
explanation. The main purpose of this editorial is to identify them and
free authors from the hitherto tiresome requirement to define them in
every paper. Those in the tables that follow – which will be updated
from time to time – may in future be used in this Journal without
explanation.
All other abbreviations should be defined. Previously published usage
should be followed unless it is manifestly clumsy or inappropriate.
Where it is necessary to devise new abbreviations and symbols, the
general principles behind established examples should be followed.
Thus, new amino-acid symbols should be of form Abc, with due thought
for possible ambiguities (Dap might be obvious for diaminoproprionic
acid, for example, but what about diaminopimelic acid?).
Where alternatives are indicated below, the first is preferred.

Amino Acids
Proteinogenic Amino Acids
.

Ala Alanine A
Arg Arginine R
Asn Asparagine N
Asp Aspartic acid D
Asx Asn or Asp
Cys Cysteine C
Gln Glutamine Q
Glu Glutamic acid E
Glx Gln or Glu
Gly Glycine G
His Histidine H
Ile Isoleucine I
Leu Leucine L
Lys Lysine K
Met Methionine M
Phe Phenylalanine F
Pro Proline P
Ser Serine S
Thr Threonine T
Trp Tryptophan W

x | Amino Acids, Pept. Proteins, 2018, 42, x–xvii


c The Royal Society of Chemistry 2018
 View Online

Tyr Tyrosine Y
Val Valine V
Copyright & 1999 European Peptide Society and John Wiley & Sons, Ltd. Reproduced with
permission from J. Peptide Sci., 1999, 5, 465–471.

Other Amino Acids

Aad a-Aminoadipic acid
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP010

bAad b-Aminoadipic acid

Abu a-Aminobutyric acid
Aib a-Aminoisobutyric acid; a-methylalanine
bAla b-Alanine; 3-aminopropionic acid (avoid Bal)
Asu a-Aminosuberic acid
Aze Azetidine-2-carboxylic acid
Cha b-cyclohexylalanine
Cit Citrulline; 2-amino-5-ureidovaleric acid
Dha Dehydroalanine (also DAla)
Gla g-Carboxyglutamic acid
Glp pyroglutamic acid; 5-oxoproline (also pGlu)
Hph Homophenylalanine (Hse = homoserine, and so on). Caution
is necessary over the use of the prefix homo in relation to
a-amino-acid names and the symbols for homo-analogues.
When the term first became current, it was applied to
analogues in which a side-chain CH2 extension had been
introduced. Thus homoserine has a side-chain CH2CH2OH,
homoarginine CH2CH2CH2NHC(¼NH)NH2, and so on.
In such cases, the convention is that a new three-letter symbol
for the analogue is derived from the parent, by taking H for
homo and combining it with the first two characters of the
.

parental symbol – hence, Hse, Har and so on. Now, however,

there is a considerable literature on b-amino acids which are
analogues of a-amino acids in which a CH2 group has been
inserted between the a-carbon and carboxyl group. These
analogues have also been called homo-analogues, and there
are instances for example not only of ‘homophenylalanine’,
NH2CH(CH2CH2Ph)CO2H, abbreviated Hph, but also ‘homo-
phenylalanine’, NH2CH(CH2Ph)CH2CO2H abbreviated Hph.
Further, members of the analogue class with CH2 inter-
polated between the a-carbon and the carboxyl group of the
parent a-amino acid structure have been called both ‘a-homo’-
and ‘b-homo’. Clearly great care is essential, and abbreviations
for ‘homo’ analogues ought to be fully defined on every
occasion. The term ‘b-homo’ seems preferable for backbone
extension (emphasizing as it does that the residue has become
a b-amino acid residue), with abbreviated symbolism as illu-
strated by bHph for NH2CH(CH2Ph)CH2CO2H.
Hyl d-Hydroxylysine
Hyp 4-Hydroxyproline
aIle allo-Isoleucine; 2S, 3R in the L-series
Lan Lanthionine; S-(2-amino-2-carboxyethyl)cysteine

Amino Acids, Pept. Proteins, 2018, 42, x–xvii | xi

 View Online

MeAla N-Methylalanine (MeVal = N-methylvaline, and so on).

This style should not be used for a-methyl residues, for which
either a separate unique symbol (such as Aib for a-methylal-
anine) should be used, or the position of the methyl group
should be made explicit as in aMeTyr for a-methyltyrosine.
Nle Norleucine; a-aminocaproic acid
Orn Ornithine; 2,5-diaminopentanoic acid
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP010

Phg Phenylglycine; 2-aminophenylacetic acid

Pip Pipecolic acid; piperidine-s-carboxylic acid
Sar Sarcosine; N-methylglycine
Sta Statine; (3S, 4S)-4-amino-3-hydroxy-6-methyl-heptanoic acid
Thi b-Thienylalanine
Tic 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid
aThr allo-Threonine; 2S, 3S in the L-series
Thz Thiazolidine-4-carboxylic acid, thiaproline
Xaa Unknown or unspecified (also Aaa)
The three-letter symbols should be used in accord with the IUPAC-IUB
conventions, which have been published in many places (e.g. European J.
Biochem. 1984; 138: 9–37), and which are (May 1999) also available with
other relevant documents at: http://www.chem.qnw.ac.uk/iubmb/iubmb.
html#03
It would be superfluous to attempt to repeat all the detail which can be
found at the above address, and the ramifications are extensive, but a few
remarks focussing on common misuses and confusions may assist. The
three-letter symbol standing alone represents the unmodified intact
amino acid, of the L-configuration unless otherwise stated (but the
L-configuration may be indicated if desired for emphasis: e.g. L-Ala). The
.

same three-letter symbol, however, also stands for the corresponding

amino acid residue. The symbols can thus be used to represent peptides
(e.g. AlaAla or Ala-Ala = alanylalanine). When nothing is shown attached
to either side of the three-letter symbol it is meant to be understood that
the amino group (always understood to be on the left) or carboxyl group
is unmodified, but this can be emphasized, so AlaAla = H-AlaAla-OH.
Note however that indicating free termini by presenting the terminal
group in full is wrong; NH2AlaAlaCO2H implies a hydrazino group at one
end and an a-keto acid derivative at the other. Representation of a free
terminal carboxyl group by writing H on the right is also wrong because
that implies a terminal aldehyde.
Side chains are understood to be unsubstituted if nothing is shown, but a
substituent can be indicated by use of brackets or attachment by a vertical
bond up or down. Thus an O-methylserine residue could be shown as 1, 2, or 3.

xii | Amino Acids, Pept. Proteins, 2018, 42, x–xvii

 View Online

Note that the oxygen atom is not shown: it is contained in the three-
letter symbol – showing it, as in Ser(OMe), would imply that a peroxy
group was present. Bonds up or down should be used only for indicating
side-chain substitution. Confusions may creep in if the three-letter
symbols are used thoughtlessly in representations of cyclic peptides.
Consider by way of example the hypothetical cyclopeptide threonylala-
nylalanylglutamic acid. It might be thought that this compound could be
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP010

economically represented 4.

But this is wrong because the left hand vertical bond implies an ester
link between the two side chains, and strictly speaking if the right hand
vertical bond means anything it means that the two Ala a-carbons are
linked by a CH2CH2 bridge. This objection could be circumvented by
writing the structure as in 5.

But this is now ambiguous because the convention that the symbols
are to be read as having the amino nitrogen to the left cannot be imposed
on both lines. The direction of the peptide bond needs to be shown with
an arrow pointing from CO to N, as in 6.
.

Actually the simplest representation is on one line, as in 7.

Substituents and Protecting Groups

Ac Acetyl
Acm Acetamidomethyl
Adoc 1-Adamantyloxycarbonyl
Alloc Allyloxycarbonyl
Boc t-Butoxycarbonyl
Bom p-Benzyloxymethyl
Bpoc 2-(4-Biphenylyl)isopropoxycarbonyl
Btm Benzylthiomethyl
Bum p-t-Butoxymethyl
Bui i-Butyl
Bun n-Butyl
But t-Butyl
Bz Benzoyl
Bzl Benzyl (also Bn); Bzl(OMe) = 4-methoxybenzyl and so on
Cha Cyclohexylammonium salt

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Clt 2-Chlorotrityl
Dcha Dicyclohexylammonium salt
Dde 1-(4,4-Dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl
Ddz 2-(3,5-Dimethoxyphenyl)-isopropoxycarbonyl
Dnp 2,4-Dinitrophenyl
Dpp Diphenylphosphinyl
Et Ethyl
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-FP010

Fmoc 9-Fluorenylmethoxycarbonyl
For Formyl
Mbh 4,4 0 -Dimethoxydiphenylmethyl, 4,4 0 -Dimethoxybenzhydryl
Mbs 4-Methoxybenzenesulphonyl
Me Methyl
Mob 4-Methoxybenzyl
Mtr 2,3,6-Trimethyl,4-methoxybenzenesulphonyl
Nps 2-Nitrophenylsulphenyl
OA11 Allyl ester
OBt 1-Benzotriazolyl ester
OcHx Cyclohexyl ester
ONp 4-Nitrophenyl ester
OPcp Pentachlorophenyl ester
OPfp Pentafluorophenyl ester
OSu Succinimido ester
OTce 2,2,2-Trichloroethyl ester
OTcp 2,4,5-Trichlorophenyl ester
Tmob 2,4,5-Trimethoxybenzyl
Mtt 4-Methyltrityl
Pac Phenacyl, PhCOCH2 (care! Pac also = PhCH2CO)
Ph Phenyl
.

Pht Phthaloyl
Scm Methoxycarbonylsulphenyl
Pmc 2,2,5,7,8-Pentamethylchroman-6-sulphonyl
Pri i-Propyl
Prn n-Propyl
Tfa Trifluoroacetyl
Tos 4-Toluenesulphonyl (also Ts)
Troc 2,2,2-Trichloroethoxycarbonyl
Trt Trityl, triphenylmethyl
Xan 9-Xanthydryl
Z Benzyloxycarbonyl (also Cbz). Z(2C1) = 2-chlorobenzyl-
oxycarbonyl and so on
Amino Acid Derivatives
DKP Diketopiperazine
NCA N-Carboxyanhydride
PTH Phenylthiohydantoin
UNCA Urethane N-carboxyanhydride
Reagents and Solvents
BOP 1-Benzotriazolyloxy-tris-dimethylamino-phosphonium
hexafluorophosphate

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 View Online

CDI Carbonyldiimidazole
DBU Diazabicyclo[5.4.0]-undec-7-ene
DCCI Dicyclohexylcarbodiimide (also DCC)
DCHU Dicyclohexylurea (also DCU)
DCM Dichloromethane
DEAD Diethyl azodicarboxylate (DMAD = the dimethyl analogue)
DIPCI Diisopropylcarbodiimide (also DIC)
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DIPEA Diisopropylethylamine (also DIEA)

DMA Dimethylacetamide
DMAP 4-Dimethylaminopyridine
DMF Dimethylformamide
DMS Dimethylsulphide
DMSO Dimethylsulphoxide
DPAA Diphenylphosphoryl azide
EEDQ 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
HATU This is the acronym for the ‘uronium’ coupling reagent
derived from HOAt, which was originally thought to
have the structure 8, the Hexafluorophosphate salt of the
O-(7-Azabenzotriazol-lyl)-Tetramethyl Uronium cation.

In fact this reagent has the isomeric N-oxide structure 9 in

the crystalline state, the unwieldy correct name of which
.

does not conform logically with the acronym, but the

acronym continues in use.

Similarly, the corresponding reagent derived from HOBt has

the firmly attached label HBTU (the tetrafluoroborate salt is
also used: TBTU), despite the fact that it is not actually a
uronium salt.
HMP Hexamethylphosphoric triamide (also HMPA, HMPTA)
HOAt 1-Hydroxy-7-azabenzotriazole
HOBt 1-Hydroxybenzotriazole
HOCt 1-Hydroxy-4-ethoxycarbonyl-1,2,3-triazole
NDMBA N,N 0 -Dimethylbarbituric acid
NMM N-Methylmorpholine
PAM Phenylacetamidomethyl resin
PEG Polyethylene glycol

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PtBOP 1-Benzotriazolyloxy-tris-pyrrolidinophosphonium
hexafluorophosphate
SDS Sodium dodecyl sulphate
TBAF Tetrabutylammonium fluoride
TBTU See remarks under HATU above
TEA Triethylamine
TFA Trifluoroacetic acid
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TFE Trifluoroethanol
TFMSA Trifluoromethanesulphonic acid
THF Tetrahydrofuran
WSCI Water soluble carbodiimide: 1-ethyl-3-(3 0 -dimethylamino-
propyl)-carbodiimide hydrochloride (also EDC)
Techniques
CD Circular dichroism
COSY Correlated spectroscopy
CZE Capillary zone electrophoresis
ELISA Enzyme-linked immunosorbent assay
ESI Electrospray ionization
ESR Electron spin resonance
FAB Fast atom bombardment
FT Fourier transform
GLC Gas liquid chromatography
hplc High performance liquid chromatography
IR Infra red
MALDI Matrix-assisted laser desorption ionization
MS Mass spectrometry
NMR Nuclear magnetic resonance
.

nOe Nuclear Overhauser effect

NOESY Nuclear Overhauser enhanced spectroscopy
ORD Optical rotatory dispersion
PAGE Polyacrylamide gel electrophoresis
RIA Radioimmunoassay
ROESY Rotating frame nuclear Overhauser enhanced spectroscopy
RP Reversed phase
SPPS Solid phase peptide synthesis
TLC Thin layer chromatography
TOCSY Total correlation spectroscopy
TOF Time of flight
UV Ultraviolet
Miscellaneous
Ab Antibody
ACE Angiotensin-converting enzyme
ACTH Adrenocorticotropic hormone
Ag Antigen
AIDS Acquired immunodeficiency syndrome
ANP Atrial natriuretic polypeptide
ATP Adenosine triphosphate
BK Bradykinin

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BSA Bovine serum albumin

CCK Cholecystokinin
DNA Deoxyribonucleic acid
FSH Follicle stimulating hormone
GH Growth hormone
HIV Human immunodeficiency virus
LHRH Luteinizing hormone releasing hormone
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MAP Multiple antigen peptide

NPY Neuropeptide Y
OT Oxytocin
PTH Parathyroid hormone
QSAR Quantitative structure–activity relationship
RNA Ribonucleic acid
TASP Template-assembled synthetic protein
TRH Thyrotropin releasing hormone
VIP Vasoactive intestinal peptide
VP Vasopressin

J. H. Jones
.

Amino Acids, Pept. Proteins, 2018, 42, x–xvii | xvii

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Scheme 3

cancer, addiction, and multiple mental diseases. A new class of amino

acid mimics (boramino acids) (Scheme 3) are described that can serve as
Published on 29 November 2017 on http://pubs.rsc.org | doi:10.1039/9781788010627-00001

general imaging probes for amino acid transporters and show strong
amino acid transporter specificity, can be labelled easily with 18F-
fluorination, and should find wide application in the development of
previously unavailable PET imaging probes for clinical diagnosis.85
The enzyme 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase is
the first one which is responsible for the synthesis of aromatic amino
acids in bacteria and plants, and a potential target for the development of
antibiotics and herbicides. The enzyme from Mycobacterium tuberculosis
displays an allosteric regulation with three interdependent allosteric
binding sites and a ternary allosteric response to combinations of the
aromatic amino acids L-Trp, L-Phe, and L-Tyr. The binding mode of
D-amino acids was investigated using X-ray crystallography, site directed
mutagenesis, and isothermal titration calorimetry, and the key differ-
ences in the binding mode were identified.86
The syntheses and photophysical characterization of three novel
cyanotryptophans (6- and 7-cyano Trp, and N-methyl-7-cyano Trp) and
their efficient incorporation into proteins as fluorescent probes are
described. 6-Cyano Trp was also incorporated into two DNA binding
proteins and an RNA recognition motif. The novel cyanotryptophans
can be used for studying conformational changes of proteins and
DNA–protein interactions.87
.

The controlled assembly of Trpzip b-hairpins was investigated. The

results show how sensitive is peptide and protein aggregation to minor
sequence variation and that it is possible to use a photolabile non-natural
amino acid analogue of Lys to tune the rate of peptide aggregation and to
control fibrillar structure.88
Different functionalized azabicyclo[X.Y.0]alkanone derivatives of
amino acids have been developed via electrophilic transannular cycliza-
tions of 8-, 9-, and 10-membered unsaturated macrocycles to form 5,5-,
6,5-, 7,5-, and 6,6-fused bicylic amino acids. Macrocycles were obtained
by a sequence featuring peptide coupling of vinyl-, allyl-, homoallyl-,
and homohomoallylglycine building blocks followed by ring-closing
metathesis. The conformational preferences and the mechanism for the
diastereoselective formation of specific azabicycloalkanone amino acids
were also studied.89
Two pyridine-linked bis(b-cyclodextrin) copper(II) complexes have been
reported that enantioselectively hydrolyse chiral esters of amino acids. It
was demonstrated that the enantioselective hydrolysis was related to the
cooperative roles of the intramolecular flanking chiral b-cyclodextrin
cavities with the coordinated copper ion.90 Fluorescent sensors based on
semiconductor quantum dots have been investigated for enantioselective
molecular recognition. A versatile fluorescent sensor encapsulated with

Amino Acids, Pept. Proteins, 2018, 42, 1–84 | 11

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