Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein |
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Authors: | Hayouka Zvi Hurevich Mattan Levin Aviad Benyamini Hadar Iosub Anat Maes Michal Shalev Deborah E Loyter Abraham Gilon Chaim Friedler Assaf |
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Affiliation: | Institute of Chemistry, The Hebrew University of Jerusalem, Givat Ram, Israel. |
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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. |
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