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

Forfatterne ønsker å takke dr. Jumpei Morimoto og Dr. Todd Doran for verdifull assistanse. Dette arbeidet ble støttet av en kontrakt fra NHLBI (NO1-HV-00242).

En. Basics av ​​Split-and-pool Synthesis For effektivt å generere et stort antall forbindelser i fast fase, blir split-og-pool syntese ofte anvendes som en generell strategi. Som vist i figur 4, tentagel perler er først delt inn i tre deler. Hver del omsettes med et annet reagens, genererer den første rest på perlene. Etter at den første reaksjon, er alle tre porsjoner samles sammen, blandet, og så igjen delt inn i tre deler. Hver porsjon vil igjen reagere med et ann...

<ol>
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Peptid tertiære amider (Ptas) er en superfamily av peptidomimetiske oligomerer. I tillegg til den godt studerte peptider, peptoids og N-metylert peptider, en stor del av forbindelsene i denne familien forblir lite studert, majorly grunn av manglende syntetisk metode for å få tilgang til de generelle N-alkylerte peptider. Her beskriver vi en effektiv metode for å syntetisere PTAs med chirale byggeblokker avledet fra aminosyrer. Tidligere har vi rapportert å bruke en ny sub-monomer rute til syntese biblioteker av PTA...

Peptidomimetika er forbindelser som etterligner strukturen av naturlige peptider. De er utformet for å holde på bioaktivitet mens overvinne noen av problemene i forbindelse med naturlige peptider, inkludert celle permeabilitet og stabilitet mot proteolyse 1-3. På grunn av den oligomere natur av disse forbindelser, kan store syntetiske biblioteker lett nås gjennom monomere eller sub-monomere syntetiske ruter 4-7. En av de mest studerte klasser av peptidomimetika er peptoids. Peptoids er oligomerer av N-alkylerte glyciner som kan syntetiseres lett ved hjelp av en sub-monomer strategi 8, 9. Mange nyttige protein ligander har blitt identifisert fra screening store syntetisk peptoid biblioteker mot protein mål 1, 10-14. Likevel, &quot;treff&quot; identifisert fra peptoid biblioteker arkivere sjelden svært høy affinitet mot protein mål 1,10-14,22. En maJor forskjellen mellom peptoids og naturlige peptider er at de fleste av de peptoids generelt mangler evnen til å danne sekundær struktur på grunn av mangel på kirale sentre og konformasjonsforandringer begrensninger. For å løse dette problemet, ble flere strategier utviklet over det siste tiåret, i stor grad fokuserer på endring av sidekjeder som finnes på de viktigste kjeden nitrogenatomer 15-22. Nylig, har vi utviklet en ny syntetisk rute til å introdusere naturlige aminosyre sidekjeder på en peptoid ryggrad til å skape peptid tertiære amider 23. Peptid tertiære amider (Ptas) er en superfamilien peptidomimetika som inkluderer, men er ikke begrenset til peptider (R2 = H), peptoids (R1 = H) og N-metylert peptider (R 1 ≠ H, R2 = Me) . (Se figur 1) En syntetisk vei syssels naturlig forekommende aminosyrer som kilde for chiralitet og sidekjeder på45; karbon, og kommersielt tilgjengelige primære aminer for å gi N-substitusjoner. Derfor kan en større kjemisk plass enn på enkle peptider, peptoids eller N-denaturert peptider bli utforsket. Sirkulære dikroisme spektra har vist at PTA-molekyler er sterkt strukturert i løsning. Karakterisering av en av de PTA-proteinkomplekser viser tydelig at konformasjonsforandringer begrensninger av PTA er nødvendig for binding. Nylig har vi også oppdaget at noen av PTA molekyler har forbedret celle permeabilitet enn sine peptoid og peptid kolleger. Vi tror at disse PTA-biblioteker kan være en god kilde for høyaffinitets-ligander for protein mål. I denne artikkelen vil vi diskutere syntesen av en prøve ett-perle ett-forbindelsen (OBOC) PTA biblioteket i detaljer sammen med noen bedre forhold for koblingen og spalting av disse forbindelsene.

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			<td style="width:160px;">424070025</td>
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			<td height="20" style="height:21px;width:249px;">L-alanine</td>
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			<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>
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			<td>CAS:5332-73-0</td>
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			<td height="20" style="height:21px;width:249px;">2-Methoxyethylamine</td>
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			<td height="20" style="height:21px;width:249px;">N-(3-Aminopropyl)-2-pyrrolidinone</td>
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			<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>
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			<td height="21" style="height:21px;width:249px;">Piperidine</td>
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			<td style="width:160px;">A12442-AE</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>
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		<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>
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		<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>
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		<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>
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		<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>
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			<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>
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			<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

Peptidomimetika er gode kilder til protein ligander. Den oligomeric naturen av disse forbindelsene gir oss tilgang til store syntetiske biblioteker på fast fase ved hjelp av kombinatorisk kjemi. En av de mest studerte klasser av peptidomimetika er peptoids. Peptoids er lette å syntetisere og har vist seg å være proteolyse bestandige og celle-gjennomtrengelig. I løpet av det siste tiåret, har mange nyttige protein ligander blitt identifisert gjennom screening av peptoid biblioteker. Men de fleste av de ligander identifisert fra peptoid bibliotekene ikke vise høy affinitet, med sjeldne unntak. Dette kan skyldes delvis mangel på kirale sentre og conformational begrensninger i peptoid molekyler. Nylig, beskrev vi en ny syntetisk rute for å få tilgang peptid tertiære amider (Ptas). PTAs er en superfamilie av peptidomimetika som inkluderer, men er ikke begrenset til peptider, peptoids og N-metylert peptider. Med sidekjeder på både α-karbon-og hovedkjede nitrogenatomer,konformasjon av disse molekylene er sterkt begrenset av sterisk hindring og allylisk 1,3 belastning. (Figur 1) En studie antyder at disse PTA-molekyler er sterkt strukturert i løsning, og kan brukes til å identifisere protein ligander. Vi tror at disse molekylene kan være en som fremtidig høyaffinitets-protein ligander. Her beskriver vi syntetisk metode som kombinerer kraften i både split-and-pool og sub-monomer strategier for å syntetisere en prøve ett-perle ett-forbindelsen (OBOC) bibliotek av PTAs.

Her viser vi tre representative MALDI spektrum fra en PTA trimer med linker. Som vist i figur 6A, når spaltet ved romtemperatur ved anvendelse av 50% TFA / DCM-løsning, er signifikant nedbrytning observert. I figur 6A, en topp 593 og 484 samsvarer med linkeren og PTA trimer henholdsvis, viser at hele molekylet ble med hell syntetisert på vulsten, men nedbrytes under spalting. Når spaltes ved lav temperatur stand som beskrevet ovenfor, er mengden av TFA-indusert nedbrytning i stor gr...

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

Peptid tertiære amider (Ptas) er en superfamilie av peptidomimetika som inkluderer, men er ikke begrenset til peptider, peptoids og N-metylert peptider. Her beskriver vi en syntetisk metode som kombinerer både split-and-pool og sub-monomer strategier for å syntetisere en ett-perle ett sammensatt bibliotek av PTAs.

Split-and-pool Syntese og karakterisering av Peptide Tertiær Amide Library

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

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