Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein

Zvi Hayouka, Mattan Hurevich, Aviad Levin, Hadar Benyamini, Anat Iosub, Michal Maes, Deborah E. Shalev, Abraham Loyter, Chaim Gilon, Assaf Friedler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Restricting linear peptides to their bioactive conformation is an attractive way of improving their stability and activity. We used a cyclic peptide library with conformational diversity for selecting an active and stable peptide that mimics the structure and activity of the HIV-1 integrase (IN) binding loop from its cellular cofactor LEDGF/p75 (residues 361-370). All peptides in the library had the same primary sequence, and differed only in their conformation. Library screening revealed that the ring size and linker structure had a huge effect on the conformation, binding and activity of the peptides. One of the cyclic peptides, c(MZ 4-1), was a potent and stable inhibitor of IN activity in vitro and in cells even after 8 days. The NMR structure of c(MZ 4-1) showed that it obtains a bioactive conformation that is similar to the parent site in LEDGF/p75.

Original languageAmerican English
Pages (from-to)8388-8395
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number23
DOIs
StatePublished - 1 Dec 2010

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 n° 203413. A.L. is supported by the Israel Science Foundation (ISF; Grant No. 888/05 ). H.B is supported by a fellowship from the Israel Cancer research Foundation (ICRF). Some molecular graphics images were produced using the Chimera package from the University of California, San Francisco (supported by NIH P41 RR-01081).

Keywords

  • Cyclic peptides
  • HIV-1
  • Intergase inhibitors
  • NMR
  • Protein mimetics
  • Protein-protein interactions

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