Alkenyl Amino Acids for Stapled Peptides HEADING_TITLE

Stapled peptides are promising intracellular drug targets.  They may have increased target affinity, cell penetrating ability and increased proteolyic resistance in comparison to non-stapled analogs  (GL Verdine, GJ Hilinski Methods Enzymol. 2012, 503, 3-33). 

Stapled peptides are formed by incorporating special amino acids with olefinic side chains at the i, i+4 positions (one-loop staple) or at i, i+7 positions (two-loop staple).  The hydrocarbon bridge is formed by a ring-closing metathesis reaction catalyzed by benzylidenebis(tricyclohexyl-phosphine)-dichlororuthenium (Grubb’s catalyst).

AAPPTec supplies a wide selection of high purity Fmoc-alkenyl alanines used to prepare stapled peptides through a ring-closing metathesis reaction.  AAPPTec’s products are affordably priced and are also available in bulk quantities for additional savings.  Please send an e-mail to sales@aapptec.com for a quotation on larger quantities or use the On-Line Quote Request.

 

 

 

 

 

 

 

For a 1-Loop Staple, use:    For a 2-Loop Staple, use:
At position i: 

UFA120 or UFA220;

UFG101 or UFG201

  At position i:

UFA121, UFA221 or UFA025;

UFG103 or UFG203  

At position i+4:

UFA121, UFA221 or UFA025;

UFG103 or UFG203

  At position i+7:

UFA122 or UFA222;

UFG104 or UFG204

         
At position i: 

UFA121, UFA221 or UFA025;

UFG103 or UFG203 

  At position i:

UFA122 or UFA222;

UFG104 or UFG204

At position i+4: 

UFA120 or UFA220;

UFG101 or UFG201 

  At position i+7:

UFA121, UFA221 or UFA025;

UFG103 or UFG203

         
At position i: 

UFA123 or UFA223;

UFG102 or UFG202

  At position i:

UFA124 or UFA224

UFG105 or UFG205

At position i+4:

UFA123 or UFA223;

UFG102 or UFG202

  At position i+7:

UFA125 or UFA225

UFG106 or UFG206

 

Stapled Peptides

In the mid-1990’s, Gregory Verdine and Christian Schafmeister began the early work on stapled peptides.  They designed a hydrocarbon staple that locked peptides into an alpha-helix conformation.  They showed that these stapled peptides were capable of resisting protease activity.  Since proteases rapidly degrade peptides in the bloodstream, stapled peptides have great therapeutic potential.

At the same time, Stanley Korsmeyer and Loren Walensky were examining the BID protein, which contains a short helical peptide that can trigger apoptosis.  When the peptide was prepared by itself, isolated from the rest of the protein structure, it lost its helical shape decreasing its biological activity, preventing its cellular uptake and making it susceptible to protease degradation.

Verdine collaborated with Korsmeyer and Walensky to construct a stapled version of the BID peptide.  They showed that the hydrocarbon stapled peptide retained its helical structure and was able to penetrate intact cells.  In a study with mice, the stapled peptide was shown to enter leukemia cells, target BCL-2 family proteins and trigger apoptosis.

Stapled peptides are good drug leads due to these features:

  • Retain active conformation
  • Permeate cell membranes
  • Resist proteolysis for longer duration

 

Optimized stapled peptides are in late-stage pre-clinical studies. (Wolfson W., Chemistry and Biology, 2009, 16, 910-2.)

Stapled peptides are prepared by ring closing metathesis of special building blocks containing alkenyl chains. (Schafmeister C, Po J, Verdine G. J. Am. Chem. Soc. 2000, 122, 5891).