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 vil gerne takke Dr. Jumpei Morimoto og Dr. Todd Doran for værdifuld hjælp. Dette arbejde blev støttet af en kontrakt fra NHLBI (NO1-HV-00242).

1.. Grundlæggende om Split-og-pool Synthesis For effektivt at generere et stort antal forbindelser på fast fase, er split-og-pool syntese ofte som en generel strategi. Som vist i figur 4, Tentagel perler først opdelt i tre portioner. Hver portion reageres med en anden reagens, der genererer den første rest på perler. Efter den første reaktion, er alle tre dele samles sammen, blandet og derefter igen opdelt i tre portioner. Hver portion igen vil reagere med et andet reage...

<ol>
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Peptid tertiære amider (ESP) er en superfamilie af peptidomimetiske oligomerer. Udover de velundersøgte peptider, peptoider og N-methylerede peptider, en stor del af forbindelser inden for denne familie er understudied, majorly på grund af manglende syntetisk metode til at få adgang til generelle N-alkylerede peptider. Her beskriver vi en effektiv metode til at syntetisere PTAs med chirale byggesten afledt af aminosyrer. Vi har tidligere rapporteret at bruge et nyt sub-monomer rute til syntese biblioteker af PTA mol...

Peptidomimetika er forbindelser, der efterligner strukturen af ​​naturlige peptider. De er designet til at bevare bioaktiviteten mens overvinde nogle af de problemer, der er forbundet med naturlige peptider, herunder cellepermeabilitet og stabilitet over for proteolyse 1-3. På grund af den oligomere natur af disse forbindelser, kan store syntetiske biblioteker let tilgås via monomere eller sub-monomere synteseveje 4-7. En af de mest undersøgte klasser af peptidomimetika er peptoider. Peptoider er oligomerer af N-alkylerede glyciner, der kan syntetiseres let ved hjælp af en sub-monomer strategi 8, 9. Mange nyttige proteinligander succes er blevet identificeret fra screening store syntetisk peptoid biblioteker mod protein-targets 1, 10-14. Ikke desto mindre, &quot;hits&quot; identificeret fra peptoid biblioteker sjældent arkivere meget høj affinitet til protein-targets 1,10-14,22. Én major forskellen mellem peptoider og naturlige peptider er, at de fleste af peptoider generelt mangler evnen til at danne sekundær struktur på grund af manglen på chirale centre og konformationelle begrænsninger. For at løse dette problem, blev der flere strategier udviklet i løbet af det sidste årti, hovedsagelig med fokus på ændring af sidekæder indeholdt på de vigtigste kæde nitrogenatomerne 15-22. For nylig har vi udviklet et nyt syntetisk vej til at indføre naturlige aminosyre sidekæder på en peptoid rygrad til at skabe peptid tertiære amider 23. Peptid tertiære amider (ESP) er en superfamilie af peptidefterligninger, der omfatter, men er ikke begrænset til peptider (R2 = H), peptoider (R1 = H) og N-methylerede peptider (R1 ≠ H, R2 = Me) . (Se figur 1) Vores syntesevej beskæftiger naturligt forekommende aminosyrer som kilde til chiralitet og sidekæder på45,-carbon og kommercielt tilgængelige primære aminer for at give N-substitutioner. Derfor kan udforskes en større kemisk plads end enkle peptider, peptoider eller N-methylerede peptider. Cirkulære dikroisme-spektre har vist, at PTA molekyler er meget struktureret i opløsning. Karakterisering af en af ​​PTA-proteinkomplekser viser klart, at konformationelle begrænsninger PTA er nødvendige for binding. Vi har for nylig også opdaget, at nogle af de PTA molekyler har forbedret cellepermeabilitet end deres peptoid og peptid-modparter. Vi mener, at disse PTA biblioteker kan være en god kilde af høj affinitet ligander til protein-targets. I dette papir vil vi diskutere syntesen af ​​en prøve én kugle én-forbindelsen (OBOC) PTA bibliotek i detaljer sammen med nogle bedre betingelser for kobling og spaltning af disse forbindelser.

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			<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>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>
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			<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">
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			<td height="20" style="height:21px;width:249px;">NAOD 40% solution in water</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>
			<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>
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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>
		</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>
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		<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>
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		<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

Peptidomimetika er gode kilder til protein-ligander. Oligomerforbindelse karakter af disse forbindelser gør det muligt at få adgang til store syntetiske biblioteker på fast fase ved hjælp af kombinatorisk kemi. En af de mest velundersøgte klasser af peptidomimetika er peptoider. Peptoider er lette at syntetisere og har vist sig at være proteolyse-resistent og celle-gennemtrængelig. Gennem det seneste årti har mange nyttige proteinligander blevet identificeret gennem screening af peptoid biblioteker. Men de fleste af de ligander identificeret fra peptoid biblioteker ikke vise høj affinitet, med sjældne undtagelser. Dette kan skyldes, dels manglen på chirale centre og konformationelle begrænsninger i peptoid molekyler. For nylig beskrev vi et nyt syntetisk rute for at få adgang peptid tertiære amider (pta). PTAs er en superfamilie af peptidefterligninger, der omfatter, men er ikke begrænset til peptider, peptoider og N-methylerede peptider. Med sidekæder på både α-carbon og væsentligste kæde nitrogenatomer,kropsbygning af disse molekyler er stærkt hæmmet af steriske hindring og allylisk 1,3 stamme. (Figur 1) Vores undersøgelse tyder på, at disse PTA molekyler er meget struktureret i opløsning og kan anvendes til at identificere protein-ligander. Vi mener, at disse molekyler kan være en fremtidig kilde af høj affinitet proteinligander. Her beskriver vi den syntetiske metode at kombinere kraften fra både split-og-pool og sub-monomer strategier til at syntetisere en prøve én kugle én-forbindelsen (OBOC) bibliotek af PTAs.

Her viser vi tre repræsentative MALDI spektre fra en PTA trimer med linker. Som vist i figur 6A, når spaltet ved stuetemperatur under anvendelse af 50% TFA / DCM opløsning, observeres betydelig nedbrydning. I figur 6A, toppe 593 og 484 svarer til linkeren og PTA trimer henholdsvis viser, at hele molekylet med succes blev syntetiseret på perle, men nedbrydes i løbet af spaltning. Når spaltes under lave temperaturer som beskrevet ovenfor, er mængden af TFA-induceret nedbrydning i h...

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 (ESP) er en superfamilie af peptidefterligninger, der omfatter, men er ikke begrænset til peptider, peptoider og N-methylerede peptider. Her beskriver vi en syntetisk fremgangsmåde, som kombinerer både split-and-pool og sub-monomer strategier til at syntetisere en en-perle-en-forbindelse bibliotek af PTAs.

Split-og pool Syntese og karakterisering af peptid tertiær amid 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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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

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Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation

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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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Syntese og karakterisering af supramolekylære Colloids

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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 ...