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The supramolecular chemistry of novel synthetic biomacromolecular assemblies

Dissertation (PhD)--Stellenbosch University, 2004 / ENGLISH ABSTRACT: Over the past decade peptide bola-amphiphiles have been the subject of much attention
because of their role as potential models of functionalised membranes and as new
generation surfactants. In the quest for new surfactants a peptidomimetic-based approach
was used to design a library of novel 'hybrid' bola-amphiphilic peptide surfactants
derived from sapecin B and a model symmetrical oligo-glycine bola-amphiphile. The
library was divided into different series, each one purpose-built; first, to investigate
hierarchal supramolecular architecture and, second, to investigate potential antimicrobial
activity. The bola-amphiphiles were synthesised using Fmoc-polyamide based solid phase
peptide synthesis and purified via high performance liquid chromatography. The peptide
hybrids were characterised using electro spray mass spectrometry, nuclear magnetic
resonance, different modes of electron microscopy, Fourier-transform infrared
spectroscopy and, in some cases, further studies were done using circular dichroism and
bioactivity tests.
The model bola-amphiphile suberamide(GGh was synthesised using peptide fragment
condensation based on solid phase peptide synthesis. The synthesis is bi-directional
(N~C and C~N) and versatile, making it possible to synthesis new dicarboxylic
oligopeptide bola-amphiphiles and other analogous compounds. The product,
suberarnide(GG)2, was purified using its inherent ability to self-assemble in an acidic
solution.
Novel asymmetrical bola-amphiphiles composed of dipeptide head groups linked via an
aliphatic (I)-amino acid, serving as a hydrocarbon spacer, were also synthesized. Two
small libraries of bola-amphiphiles were established - the first involved variation in
to-amino acid length and the other variation in the C-terminal amino acid. The bolaamphiphiles
were self-assembled in either 0.1% trif1uoroacetic acid or 0.1%
triethylamine. Electron microscopy revealed the formation of a variety of higher order
supramolecular architectures based on ~-sheet self-assembly. FT-IR spectrometry
indicated that interlayer and intralayer hydrogen bond networks, together with strong selfassociation,
promoted by the hydrophobic effect and, in certain instances, electrostatic
interactions, are responsible for the variety of supramolecular architectures. Variations in the higher order structures can be attributed to amino acid composition, specifically
length of m-amino acid, nature of the C-terminal amino acid and the optimised solvent
conditions used for the self-assembly process.
A third library of novel 'hybrid' bola-amphiphilic peptide surfactants, in which a cationic
tripeptide motif from antimicrobial peptides was combined in a hybrid molecule
containing a oi-amino acid residue, was established. These bola-amphiphiles displayed
potent antimicrobial activity against both Gram-positive and Gram-negative bacteria; the
analogues were as active or more active than the leader peptides yet, remarkably,
displayed little or no appreciable haemolytic activity. These organopeptide bolaamphiphiles
thus demonstrated selective toxicity towards bacteria. The hydrophobicity
imparted by the co-amino acid has contrasting effects on haemolysis and antimicrobial
activity of the peptide analogues. The other unique feature of these peptides and their
analogues is the fact they self-assembled into complex supramolecular architectures,
composed primarily of ~-sheets. Their self-assembly is primarily governed by
hydrophobic interactions together with inter and intralayer hydrogen bonding. Electron
microscopy clearly revealed higher order structures for both peptides and analogues. The
generation of higher order supramolecular architecture is dependent on optimisation of ~-
sheet self-assembly whereas antimicrobial activity is dependent on the balance between
net positive charge and optimum hydrophobicity of the peptide hybrids.
This study has demonstrated that it is possible to design hybrid peptide surfactants
capable of producing higher order supramolecular architecture and improving the
antimicrobial activity whilst reducing the haemolytic effect. The study and design of
these versatile 'purpose-built' bio-inspired surfactants heralds a novel approach, one that
shows tremendous potential. / AFRIKAANSE OPSOMMING: Die afgelope dekade het bola-amfifiliese peptiede baie aandag geniet weens hulle rolle as
potensiële modelle van gefunksionaliseerde membrane en as 'n nuwe generasie
surfaktante. In die soeke na nuwe surfaktante is 'n peptiedornimetiese benadering gevolg
om 'n biblioteek van nuwe "hibried" bola-amfifiliese peptiedsurfaktante van sapesien B
en 'n simmetriese oligoglisien bola-amfifil af te lei. Die biblioteek is in verskillende
reekse onderverdeel. Elke reeks is doelmatig vervaardig om ondersoek in te stel na twee
aspekte, nl. die rangorde van die supramolekulêre strukture en die potensiële
antirnikrobiese aktiwiteit. Fmoc-poliamied gebaseerde soliedefase-peptied-sin-tese is
aangewend vir die sintese van die bola-amfifile en hulle is met behulp van hoë
doeltreffendheid vloeistofchromatografie gesuiwer. Die peptiedhibriede is gekarakteriseer
met behulp van elekrosproei massaspektrometrie, kern-magnetiese resonansie,
verskillende modusse elektronrnikroskopie, Fourier-transform infrarooispektrometrie en,
in sommige gevalle is verdere studies met sirkulêre dichroïsme en bioaktiwiteitstoetsing
uitgevoer.
Die bola-amfifilsuberamiedtflfij--model is met behulp van peptiedfragment-konden-sasie
gesintetiseer gegrond op soliedefase-peptiedsintese. Dit sintese vind in twee rigtings plaas
(N~C en C~N) en is veelsydig aangesien dit die sintese van sowel nuwe dikar-boksielbola-
amfifile as ander analoë verbindings moontlik maak. Die produk, suber-arnied(GG)2,
is gesuiwer met behulp van die verbinding se inherente vermoë tot self-montering in suur
oplossings.
Nuwe assimetriese bola-amfifile, saamgestel uit dipeptiedkopgroepe, gekoppel via 'n
alifatiese ro-aminosuur, wat as koolwaterstofspasieerder dien, is ook gesintetiseer. Twee
klein bola-amfifilbiblioteke is saamgestel - die een het variasies in die ro-aminosuur se
lengte omvat en die ander een variasies in die C-terrninale aminosuur. Selfmontering van
die bola-amfifile het plaasgevind in of 0,1 % trifluorasynsuur Of 0,1 % trietielamien.
Elektronrnikroskopie het die bestaan van 'n verskeidenheid hoërorde supramolekulêre
strukture, gegrond op p-plaatselfmontering, aangetoon. Uit FT-IR-spektrometrie blyk dit
dat inter - en intralaag waterstofbinbdingsnetwerke en sterk selfassosiasie, 19. word
bevorder deur die hidrofobiese effek en, in sekere gevalle, elektrostatiese interaksies, is
verantwoordelik vir die verskeidenheid supramolekulêre strukture. Variasies in die hoërorde strukture kan toegeskryf word aan aminosuursamestelling, in besonder die
lengte van die ro-aminosuur, die aard van die C-terminale aminosuur en die geoptimiseerde
oplosmiddelkondisies wat gebruik is vir die selfmonteringsproses.
'n Derde biblioteek nuwe "hibried" bola-amfifiliese peptiedsurfaktante, waarin 'n kationiese
tripeptiedmotief uit antimikrobiale peptiede gekombineer is met 'n m-aminosuurresidu,
is geskep. Sommige van hierdie bola-amfifile het 'n kragtige antimikrobiese
aktiwiteit teenoor sowel Gram-positiewe as Gram-negatiewe bakterieë gertoon. Die
analoë strukture was aktief, of selfs meer aktief as die voorste peptiede maar het,
verbasend genoeg, nie 'n beduidende hemolitiese aktiwiteit vertoon nie. Hierdie
organopeptied bola-amfifil het dus 'n selektiewe toksisiteit teenoor bakterieë vertoon. Die
hidrofo-bisiteit, as gevolg van die ui-aminosuur, het 'n resiproke effek op hemolise en die
antimikrobiese aktiwiteit van die peptiedanaloë. Die ander uitstaande kenmerk van die
peptiede en hulle analoë is die vermoë om te selfmonteer en komplekse supramolekulêre
strukture, bestaande hoofsaaklik uit ~-plate, te vorm. Hierdie selfmontering word in
hoofsaak beheer deur hidrofobiese interaksies asook inter - en intralaagwaterstofbinding.
Elektronmikroskopie het duidelik hoërorde strukture getoon by sowel dié peptiede as
hulle analoë. Die ontwikkeling van hoërorde supramolekulêre struktuurvorms is afhanklik
van die optimalisering van die ~-plaatselfmontering. Daarteenoor is die antimikro-biese
aktiwiteit afhanklik van die balans tussen die netto positiewe lading en die opti-male
hidrofobisiteit van die peptiedhibriede.
Hierdie studie het getoon dat dit moontlik is om hibriedsurfaktante te ontwerp wat
hoërorde supramolekulêre strukture te produseer en om die antimikrobiese aktiwiteit te
verbeter terwyl die hemolitiese effek verminder word. Die studie en ontwerp van hier-die
veeldoelige, "doelmatig-gesintetiseerde" biogeïnspireerde surfakante stel 'n unieke
benadering daar, wat oor groot potensiaal beskik.

Identiferoai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/50196
Date04 1900
CreatorsNaidoo, Venthan B.
ContributorsSanderson, R. D., Rautenbach, M., Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Sciences.
PublisherStellenbosch : Stellenbosch University
Source SetsSouth African National ETD Portal
Languageen_ZA
Detected LanguageUnknown
TypeThesis
Format[111] p. : ill.
RightsStellenbosch University

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