Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein.
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.
Institute of Chemistry, The Hebrew University of Jerusalem, Givat Ram, Israel.
Zvi
Z
Hayouka
Mattan
M
Hurevich
Aviad
A
Levin
Hadar
H
Benyamini
Anat
A
Iosub
Michal
M
Maes
Deborah E
DE
Shalev
Abraham
A
Loyter
Chaim
C
Gilon
Assaf
A
Friedler
D000595:Amino Acid Sequence; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014779:Virus Replication / Q000187:drug effects
D019428:HIV Integrase Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D010456:Peptides, Cyclic; C119380:lens epithelium-derived growth factor; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1