title: A comparative study of backbone versus side chain peptide cyclization: application for HIV-1 integrase inhibitors.
abstract: 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.
authors.affiliation: Institute of Chemistry, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem 91904, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Hayouka
authors.forename: Aviad
authors.initials: A
authors.lastname: Levin
authors.forename: Mattan
authors.initials: M
authors.lastname: Hurevich
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Shalev
authors.forename: Abraham
authors.initials: A
authors.lastname: Loyter
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
authors.forename: Assaf
authors.initials: A
authors.lastname: Friedler
mesh_terms: D000595:Amino Acid Sequence; D004789:Enzyme Activation / Q000187:drug effects; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019428:HIV Integrase Inhibitors; D019151:Peptide Library; D010456:Peptides, Cyclic