Stapled peptide: Difference between revisions
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[[File:4MZK stapled peptide.png|thumb|right|A cartoon depiction of a stapled peptide. The red coloring depicts a helix, and the green coloring denotes the hydrocarbon staple. Rendering based on [[Protein_Data_Bank | PDB]] {{PDB2|4MZK}}.<ref name=pmid25084543>{{cite journal|last1=Douse|first1=CH|last2=Maas|first2=SJ|last3=Thomas|first3=JC|last4=Garnett|first4=JA|last5=Sun|first5=Y|last6=Cota|first6=E|last7=Tate|first7=EW|title=Crystal structures of stapled and hydrogen bond surrogate peptides targeting a fully buried protein-helix interaction.|journal=ACS chemical biology|date=17 October 2014|volume=9|issue=10|pages=2204-9|pmid=25084543|accessdate=22 July 2015}}</ref>]] |
[[File:4MZK stapled peptide.png|thumb|right|A cartoon depiction of a stapled peptide. The red coloring depicts a helix, and the green coloring denotes the hydrocarbon staple. Rendering based on [[Protein_Data_Bank | PDB]] {{PDB2|4MZK}}.<ref name=pmid25084543>{{cite journal|last1=Douse|first1=CH|last2=Maas|first2=SJ|last3=Thomas|first3=JC|last4=Garnett|first4=JA|last5=Sun|first5=Y|last6=Cota|first6=E|last7=Tate|first7=EW|title=Crystal structures of stapled and hydrogen bond surrogate peptides targeting a fully buried protein-helix interaction.|journal=ACS chemical biology|date=17 October 2014|volume=9|issue=10|pages=2204-9|pmid=25084543|accessdate=22 July 2015}}</ref>]] |
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A '''stapled peptide''' is a [[peptide]] that has a synthetic brace ("staple"). Tandem staples on a peptide are sometimes referred to as '''stitched peptides'''.<ref name=pmid22230563>{{cite journal|last1=Verdine|first1=GL|last2=Hilinski|first2=GJ|title=Stapled peptides for intracellular drug targets.|journal=Methods in enzymology|date=2012|volume=503|pages=3-33|pmid=22230563|accessdate=22 July 2015}}</ref> Peptide stapling is used to enhance [[pharmacologic]] performance of peptides.<ref name=pmid22230563></ref> |
A '''stapled peptide''' is a [[peptide]] that has a synthetic brace ("staple"). Tandem staples on a peptide are sometimes referred to as '''stitched peptides'''.<ref name=doic4md00131a>{{cite journal|last1=Chu|first1=Qian|last2=Moellering|first2=Raymond E.|last3=Hilinski|first3=Gerard J.|last4=Kim|first4=Young-Woo|last5=Grossmann|first5=Tom N.|last6=Yeh|first6=Johannes T.-H.|last7=Verdine|first7=Gregory L.|title=Towards understanding cell penetration by stapled peptides|journal=Med. Chem. Commun.|date=2015|volume=6|issue=1|pages=111–119|doi=10.1039/c4md00131a|accessdate=22 July 2015}}</ref><ref name=pmid22230563>{{cite journal|last1=Verdine|first1=GL|last2=Hilinski|first2=GJ|title=Stapled peptides for intracellular drug targets.|journal=Methods in enzymology|date=2012|volume=503|pages=3-33|pmid=22230563|accessdate=22 July 2015}}</ref> Peptide stapling is used to enhance [[pharmacologic]] performance of peptides.<ref name=pmid22230563></ref> |
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==Introduction== |
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The two primary classes of therapeutics are [[small molecules]] and [[Biopharmaceutical|protein therapeutics]]. It is difficult to [[Drug design|design]] small molecule inhibitors of [[Protein–protein interaction|protein protein interactions]]<ref>{{cite journal|last1=Arkin|first1=Michelle R.|last2=Wells|first2=James A.|title=Small-molecule inhibitors of protein–protein interactions: progressing towards the dream|journal=Nature Reviews Drug Discovery|date=April 2004|volume=3|issue=4|pages=301–317|doi=10.1038/nrd1343}}</ref> and protein therapeutics have poor cell penetration due to insufficient ability to diffuse across the [[cell membrane]]. Additionally, protein and peptides are often subject to [[proteolytic degradation]]. Furthermore, small peptides (such as single [[Alpha helix|alpha-helices]]) [[Alpha helix#Stability|do not exhibit helicity in solution]] due to [[entropic]] factors: this effect diminishes [[binding affinity]].<ref name=pmid22230563></ref> |
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Introducing a synthetic brace (staple) helps to lock a peptide in a specific conformation reducing [[conformational entropy]]. This approach can increase target affinity, increase cell penetration, and protect against proteolytic degradation. <ref name=pmid22230563></ref><ref name=pmid24601557>{{cite journal|last1=Walensky|first1=LD|last2=Bird|first2=GH|title=Hydrocarbon-stapled peptides: principles, practice, and progress.|journal=Journal of medicinal chemistry|date=14 August 2014|volume=57|issue=15|pages=6275-88|pmid=24601557|accessdate=22 July 2015}}</ref> |
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==References== |
==References== |
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==See Also== |
==See Also== |
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* [[Druggability]] |
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* [[Non-proteinogenic amino acids]] |
* [[Non-proteinogenic amino acids]] |
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* [[Peptide synthesis]] |
* [[Peptide synthesis]] |
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Revision as of 16:20, 22 July 2015
A stapled peptide is a peptide that has a synthetic brace ("staple"). Tandem staples on a peptide are sometimes referred to as stitched peptides.[2][3] Peptide stapling is used to enhance pharmacologic performance of peptides.[3]
Introduction
The two primary classes of therapeutics are small molecules and protein therapeutics. It is difficult to design small molecule inhibitors of protein protein interactions[4] and protein therapeutics have poor cell penetration due to insufficient ability to diffuse across the cell membrane. Additionally, protein and peptides are often subject to proteolytic degradation. Furthermore, small peptides (such as single alpha-helices) do not exhibit helicity in solution due to entropic factors: this effect diminishes binding affinity.[3]
Introducing a synthetic brace (staple) helps to lock a peptide in a specific conformation reducing conformational entropy. This approach can increase target affinity, increase cell penetration, and protect against proteolytic degradation. [3][5]
References
- ^ Douse, CH; Maas, SJ; Thomas, JC; Garnett, JA; Sun, Y; Cota, E; Tate, EW (17 October 2014). "Crystal structures of stapled and hydrogen bond surrogate peptides targeting a fully buried protein-helix interaction". ACS chemical biology. 9 (10): 2204–9. PMID 25084543.
{{cite journal}}:|access-date=requires|url=(help) - ^ Chu, Qian; Moellering, Raymond E.; Hilinski, Gerard J.; Kim, Young-Woo; Grossmann, Tom N.; Yeh, Johannes T.-H.; Verdine, Gregory L. (2015). "Towards understanding cell penetration by stapled peptides". Med. Chem. Commun. 6 (1): 111–119. doi:10.1039/c4md00131a.
{{cite journal}}:|access-date=requires|url=(help) - ^ a b c d Verdine, GL; Hilinski, GJ (2012). "Stapled peptides for intracellular drug targets". Methods in enzymology. 503: 3–33. PMID 22230563.
{{cite journal}}:|access-date=requires|url=(help) - ^ Arkin, Michelle R.; Wells, James A. (April 2004). "Small-molecule inhibitors of protein–protein interactions: progressing towards the dream". Nature Reviews Drug Discovery. 3 (4): 301–317. doi:10.1038/nrd1343.
- ^ Walensky, LD; Bird, GH (14 August 2014). "Hydrocarbon-stapled peptides: principles, practice, and progress". Journal of medicinal chemistry. 57 (15): 6275–88. PMID 24601557.
{{cite journal}}:|access-date=requires|url=(help)