A comparative study of backbone versus side chain peptide cyclization: Application for HIV-1 integrase inhibitors

Zvi Hayouka, Aviad Levin, Mattan Hurevich, Deborah E. Shalev, Abraham Loyter, Chaim Gilon, Assaf Friedler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Peptide cyclization is an important tool for overcoming the limitations of linear peptides as drugs. Backbone cyclization (BC) has advantages over side chain (SC) cyclization because it combines N-alkylation for extra peptide stability. However, the appropriate building blocks for BC are not yet commercially available. This problem can be overcome by preparing SC cyclic peptide analogs of the most active BC peptide using commercially available building blocks. We have recently developed BC peptides that inhibit the HIV-1 integrase enzyme (IN) activity and HIV-1 replication in infected cells. Here we used this system as a model for systematically comparing the BC and SC cyclization modes using biophysical, biochemical and structural methods. The most potent SC cyclic peptide was active almost as the BC peptide and inhibited IN activity in vitro and blocked IN activity in cells even after 6 days. We conclude that both cyclization types have their respective advantages: The BC peptide is more active and stable, probably due to the N-alkylation, while SC cyclic peptides are easier to synthesize. Due to the high costs and efforts involved in preparing BC peptides, SC may be a more approachable method in many cases. We suggest that both methods are interchangeable.

Original languageAmerican English
Pages (from-to)3317-3322
Number of pages6
JournalBioorganic and Medicinal Chemistry
Issue number10
StatePublished - 15 May 2012

Bibliographical note

Funding Information:
A.F. is supported by a starting grant from the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant Agreement No 203413. A.L. was supported by the Israel Science Foundation (ISF; Grant No. 888/05). Some molecular graphics images were produced using the Chimera package from the University of California, San Francisco (supported by NIH P41 RR-01081).


  • Cyclic peptides
  • HIV-1
  • Integrase
  • Peptides


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