Name: split-and-pool synthesis and characterization of peptide tertiary amide library
Uploaded: 2014-06-20T13:00:00
Description: Watch this Scientific Journal Video about Split-and-pool Synthesis and Characterization of Peptide Tertiary Amide Library at JoVE.com

Gli autori desiderano ringraziare il Dott. Jumpei Morimoto e il Dr. Todd Doran per la preziosa assistenza. Questo lavoro è stato supportato da un contratto del NHLBI (NO1-HV-00242).

1. Nozioni di base di Split-e-pool sintesi Al fine di generare in modo efficiente un gran numero di composti in fase solida, sintesi split-e-pool è spesso impiegato come strategia generale. Come mostrato in Figura 4, tentagel perle sono prima divisa in tre porzioni. Ciascuna porzione viene fatto reagire con un reagente diverso, generando il primo residuo su perline. Dopo la prima reazione, tutte e tre le porzioni sono raggruppate, mescolati, e poi nuovamente suddivise in tre ...

<ol>
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Peptide ammidi terziarie (PTA) sono una superfamiglia di oligomeri peptidomimetici. Oltre ai peptidi ben studiato, peptoids e peptidi N-metilati, una gran parte di composti all&#39;interno di questa famiglia rimane understudied, majorly a causa della mancanza di metodo sintetico per accedere generali peptidi N-alchilati. Qui si descrive un metodo efficace per sintetizzare PTA con blocchi chirali derivati ​​da amminoacidi. In precedenza, abbiamo riportato di utilizzare un nuovo percorso sub-monomero di librerie di si...

Peptidomimetici sono composti che imitano la struttura di peptidi naturali. Essi sono progettati per mantenere la bioattività mentre superare alcuni dei problemi associati con peptidi naturali, tra cui la permeabilità cellulare e stabilità contro proteolisi 1-3. A causa della natura oligomerica di questi composti, grandi librerie sintetiche possono essere facilmente accessibili attraverso vie sintetiche monomeriche o sub-monomerici 4-7. Una delle classi più studiati di peptidomimetici è peptoids. Peptoids sono oligomeri di glicine N-alchilati, che possono essere sintetizzati facilmente usando una strategia sub-monomero 8, 9. Molti ligandi di proteine ​​utili sono stati identificati con successo da screening di librerie di grandi dimensioni peptoid sintetico contro bersagli proteici 1, 10-14. Tuttavia, &quot;hits&quot; individuati dalle biblioteche peptoid raramente archivio un&#39;elevata affinità verso gli obiettivi della proteina 1,10-14,22. One major differenza tra peptoids e peptidi naturali è che la maggior parte dei peptoids generalmente non hanno la capacità di formare strutture secondarie a causa della mancanza di centri chirali e vincoli conformazionali. Per risolvere questo problema, strategie multiple sono state sviluppate negli ultimi dieci anni, in gran parte incentrata sulla modifica delle catene laterali presenti sulle principali atomi di azoto catena 15-22. Recentemente, abbiamo sviluppato una nuova via sintetica per introdurre catene laterali di aminoacidi naturali su una dorsale peptoid per creare peptidi ammidi terziarie 23. Peptide ammidi terziarie (PTA) sono una famiglia di super-peptidomimetici che includono ma non sono limitate a peptidi (R 2 = H), peptoids (R 1 = H) e peptidi N-metilato (R 1 ≠ H, R 2 = Me) . (Vedi figura 1) La via sintetica impiega aminoacidi naturali come fonte di chiralità e catene laterali sul45;-carbonio, e ammine primarie disponibili in commercio per fornire N-sostituzioni. Pertanto, uno spazio chimico più grande di quello di peptidi semplici, peptoids o peptidi N-metilato può essere esplorato. Spettri di dicroismo circolare hanno dimostrato che le molecole del PTA sono altamente strutturati in soluzione. Caratterizzazione di uno dei complessi PTA-proteina mostra chiaramente che i vincoli conformazionali di PTA sono richiesti per il legame. Recentemente, abbiamo anche scoperto che alcune delle molecole PTA possiedono una migliore permeabilità cellulare rispetto ai loro omologhi peptoid e peptidi. Noi crediamo che queste librerie PTA possono essere una buona fonte di ligandi ad alta affinità per le proteine ​​target. In questo articolo, discuteremo la sintesi di un campione unico tallone di un composto (OBOC) biblioteca PTA in dettaglio insieme ad alcune condizioni migliori per l&#39;accoppiamento e la scissione di questi composti.

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	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">2,4,6 trimethylpyridine</td>
			<td style="width:169px;">ACROS</td>
			<td style="width:160px;">161950010</td>
			<td style="width:311px;">CAS:108-75-8</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:249px;">2-morpholinoethanamine</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">06680&#160;</td>
			<td>CAS:2038-03-1&#160;&#160;</td>
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			<td height="21" style="height:21px;width:249px;">48% HBr Water solution</td>
			<td style="width:169px;">ALFA AESAR</td>
			<td style="width:160px;">AA14036AT</td>
			<td>CAS:10035-10-6</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Acetaldehyde</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">402788</td>
			<td>CAS:75-07-0&#160;&#160;</td>
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			<td height="21" style="height:21px;width:249px;">Acetonitrile</td>
			<td style="width:169px;">Fisher</td>
			<td style="width:160px;">SR015AA-19PS</td>
			<td>CAS:75-05-8</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Anhydrous Tetrahydrofuran (THF)</td>
			<td style="width:169px;">EMD</td>
			<td style="width:160px;">EM-TX0277-6&#160;</td>
			<td>CAS:109-99-9</td>
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			<td height="21" style="height:21px;width:249px;">Benzylamine</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">185701</td>
			<td>CAS:100-46-9</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:249px;">bis(trichloromethyl) carbonate (BTC)</td>
			<td style="width:169px;">ACROS</td>
			<td style="width:160px;">258950050</td>
			<td>CAS:32315-10-9</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Bromoacetic acid</td>
			<td style="width:169px;">ACROS</td>
			<td style="width:160px;">106570010</td>
			<td>CAS:79-08-3</td>
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			<td height="21" style="height:21px;width:249px;">Chloranil</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">23290</td>
			<td>CAS:118-75-2</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Cyclohexanemethylamine</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">101842</td>
			<td>CAS:3218-02-8</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:21px;">D2O</td>
			<td style="width:169px;">Cambridge Isotope</td>
			<td style="width:160px;">DLM-4-99.8-1000</td>
			<td>CAS:7789-20-0</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:21px;width:249px;">D-alanine</td>
			<td style="width:169px;">Anaspec</td>
			<td style="width:160px;">61387-100</td>
			<td>CAS:338-69-2&#160;&#160;</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:21px;width:249px;">Dichloromethane (DCM)</td>
			<td style="width:169px;">Fisher</td>
			<td style="width:160px;">BJ-NS300-20</td>
			<td>CAS:75-09-2</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:21px;width:249px;">Dimethylformamide (DMF)</td>
			<td style="width:169px;">Fisher</td>
			<td style="width:160px;">BJ-076-4</td>
			<td>CAS:68-12-2</td>
		</tr>
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			<td height="20" style="height:21px;width:249px;">Ethylene glycol</td>
			<td style="width:169px;">Oakwood</td>
			<td style="width:160px;">44710</td>
			<td>CAS:107-21-1</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:21px;width:249px;">Isopentylamine</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">W321907</td>
			<td>CAS:107-85-7</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:21px;width:249px;">KBr</td>
			<td style="width:169px;">ACROS</td>
			<td style="width:160px;">424070025</td>
			<td>CAS:7758-02-3</td>
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		<tr height="20">
			<td height="20" style="height:21px;width:249px;">L-alanine</td>
			<td style="width:169px;">Anaspec</td>
			<td style="width:160px;">61385-100</td>
			<td>CAS:56-41-7&#160;</td>
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		<tr height="20">
			<td height="20" style="height:21px;width:249px;">3-Methoxypropylamine</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">M25007</td>
			<td>CAS:5332-73-0</td>
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		<tr height="20">
			<td height="20" style="height:21px;width:249px;">2-Methoxyethylamine</td>
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			<td style="width:160px;">143693</td>
			<td>CAS:109-85-3</td>
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		<tr height="20">
			<td height="20" style="height:21px;width:249px;">N-(3-Aminopropyl)-2-pyrrolidinone</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">136565&#160;</td>
			<td>CAS:7663-77-6&#160;</td>
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		<tr height="20">
			<td height="20" style="height:21px;width:249px;">N,N&#39;-Diisopropylcarbodiimide (DIC)</td>
			<td style="width:169px;">ACROS</td>
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			<td>CAS:693-13-0</td>
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		<tr height="20">
			<td height="20" style="height:21px;width:249px;">N,N-Diisopropylethylamine (DIPEA)</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">D125806</td>
			<td>CAS:7087-68-5</td>
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		<tr height="20">
			<td height="20" style="height:21px;">NaNO2</td>
			<td style="width:169px;">ACROS</td>
			<td style="width:160px;">424340010</td>
			<td>CAS:7631-99-4</td>
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			<td height="20" style="height:21px;width:249px;">NAOD 40% solution in water</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Piperidine</td>
			<td style="width:169px;">ALFA AESAR</td>
			<td style="width:160px;">A12442-AE</td>
			<td>CAS:110-89-4</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Piperonylamine</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">P49503&#160;</td>
			<td>CAS:2620-50-0</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Propylamine</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">240958</td>
			<td>CAS:107-10-8</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Trifluoroacetic acid</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">299537</td>
			<td>CAS:76-05-1</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">&#945;-Cyano-4-hydroxycinnamic acid&#160;</td>
			<td style="width:169px;">Sigma-Aldrich</td>
			<td style="width:160px;">39468</td>
			<td>CAS:28166-41-8&#160;&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">&#945;-ketoglutarate</td>
			<td style="width:169px;">ALFA AESAR</td>
			<td style="width:160px;">AAA10256-22</td>
			<td style="width:311px;">CAS:328-50-7</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Tentagel Resin with RINK linker</td>
			<td style="width:169px;">Rapp-Polymere</td>
			<td style="width:160px;">S30023</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Alanine transaminase</td>
			<td style="width:169px;">Roche</td>
			<td style="width:160px;">10105589001</td>
			<td>AKA: Glutamate-Pyruvate Transaminase (GPT)</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:249px;">Incubator</td>
			<td style="width:169px;">New Brunswick Scientific</td>
			<td style="width:160px;">Innova44</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">NMR</td>
			<td style="width:169px;">Bruker</td>
			<td style="width:160px;">400MHz</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">MALDI mass spectrometer</td>
			<td style="width:169px;">Applied Biosystems&#160;</td>
			<td style="width:160px;">4800 MALDI-TOF/TOF</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Lyophilizer</td>
			<td style="width:169px;">SP Scientific</td>
			<td style="width:160px;">VirTis benchtop K</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Syringe reactor</td>
			<td style="width:169px;">INTAVIS&#160;</td>
			<td style="width:160px;">Reaction Column</td>
			<td>3ml, 5ml, 10ml, 20ml</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:249px;">Vacuum manifold&#160;</td>
			<td style="width:169px;">Promega</td>
			<td style="width:160px;">A7231</td>
			<td>Vac-Man</td>
		</tr>
	</tbody>
</table>

split-and-pool synthesis and characterization of peptide tertiary amide library

Peptidomimetici sono grandi fonti di leganti proteici. La natura oligomerica di questi composti in grado di accedere a grandi librerie sintetiche su fase solida utilizzando la chimica combinatoriale. Una delle classi più ben studiati di peptidomimetici è peptoids. Peptoids sono facili da sintetizzare e hanno dimostrato di essere resistente alla proteolisi e cellula-permeabile. Negli ultimi dieci anni, molte leganti proteici utili sono stati identificati attraverso lo screening di librerie peptoid. Tuttavia, la maggior parte dei ligandi identificati dalle biblioteche peptoid non vengono visualizzati alta affinità, con rare eccezioni. Ciò può essere dovuto, in parte, alla mancanza di centri chirali e vincoli conformazionali nelle molecole peptoid. Recentemente, abbiamo descritto una nuova via sintetica per accedere peptidi ammidi terziarie (PTA). PTA sono una superfamiglia di peptidomimetici che includono ma non sono limitate a, peptidi peptoids e peptidi N-metilati. Con catene laterali su entrambi α-carbonio e atomi di azoto catena principale,la conformazione di queste molecole sono notevolmente limitata dalla impedimento sterico e allilico 1,3 ceppo. (Figura 1) Il nostro studio suggerisce che queste molecole PTA sono altamente strutturate in soluzione e possono essere utilizzati per identificare ligandi proteici. Crediamo che queste molecole possono essere una futura fonte di ligandi ad alta affinità della proteina. Qui si descrive il metodo di sintesi che unisce la potenza di entrambi split-e-pool e le strategie sub-monomeri per sintetizzare un campione unico tallone di un composto (OBOC) biblioteca di PTA.

Qui vi mostriamo tre spettri rappresentativi MALDI da un trimero PTA con linker. Come mostrato nella Figura 6A, quando spaccati a temperatura ambiente utilizzando il 50% di soluzione di TFA / DCM, degradazione significativa si osserva. In Figura 6A, picco 593 e 484 corrispondono al linker e il trimero PTA, rispettivamente, mostrano che l&#39;intera molecola è stato sintetizzato con successo sul tallone ma degradato durante scissione. Quando spaccati in condizioni di bassa temperatura c...

Watch this Scientific Journal Video about Split-and-pool Synthesis and Characterization of Peptide Tertiary Amide Library at JoVE.com

Split-and-pool Synthesis and Characterization of Peptide Tertiary Amide Library

Peptide ammidi terziarie (PTA) sono una superfamiglia di peptidomimetici che includono ma non sono limitate a peptidi, peptoids e peptidi N-metilato. Qui si descrive un metodo sintetico che combina split-e-pool e le strategie sub-monomeri per sintetizzare un one-tallone biblioteca un composto di PTA.

Split-e-pool Sintesi e caratterizzazione di peptidi Terziario Ammide Biblioteca

Peptidomimetics are great sources of protein ligands. The oligomeric nature of these compounds enables us to access large synthetic libraries on solid ...

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Carboxylic Acid Derivatives

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Nucleoside Triphosphates - From Synthesis to Biochemical Characterization

Nucleosidi trifosfati - Dalla sintesi di biochimica Caratterizzazione

The  traditional strategy for the introduction of chemical functionalities is the  use of solid-phase synthesis by appending suitably modified ...

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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

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Herein we report the synthesis of a tridentate phosphine ligand N(CH2PPh2)3 (N-triphosPh) (1) via a phosphorus based Mannich reaction of the ...

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Plasmonic nanoparticles are an attractive material for light harvesting applications due to their easily modified surface, high surface area and large ...

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Protein-protein interactions (PPIs) are intimately involved in almost all biological processes and are linked to many human diseases. Therefore, there is ...

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Control over colloidal assembly is of utmost importance for the development of functional colloidal materials with tailored structural and mechanical ...

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Sintesi di ciclici polimeri e caratterizzazione di loro moto diffusivo allo stato fuso alla molecola Piano unico

We demonstrate a method for the synthesis of cyclic polymers and a protocol for characterizing their diffusive motion in a melt state at the single ...

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The goal of the protocol is to synthesize Fe-doped aluminosilicate nanotubes of the imogolite type with the formula (OH)3Al2-xFexO3SiOH. Doping with Fe ...

Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism

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Solid-phase synthesis has been used to obtain canonical and modified polymers of nucleic acids, specifically of DNA or RNA, which has made it a popular ...