Peptide inhibitors of HIV-1 integrase: from mechanistic studies to improved lead compounds.
The HIV-1 integrase enzyme (IN) catalyzes integration of viral DNA into the host genome. We previously developed peptides that inhibit IN in vitro and HIV-1 replication in cells. Here we present the design, synthesis and evaluation of several derivatives of one of these inhibitory peptides, the 20-mer IN1. The peptide corresponding to the N-terminal half of IN1 (IN1 1-10) was easier to synthesize and much more soluble than the 20-mer IN1. IN1 1-10 bound IN with improved affinity and inhibited IN activity as well as HIV replication and integration in infected cells. While IN1 bound the IN tetramer, its shorter derivatives bound dimeric IN. Mapping the peptide binding sites in IN provided a model that explains this difference. We conclude that IN1 1-10 is an improved lead compound for further development of IN inhibitors.
Maes
Michal
M
Institute of Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel.
Levin
Aviad
A
Hayouka
Zvi
Z
Shalev
Deborah E
DE
Loyter
Abraham
A
Friedler
Assaf
A
D000595:Amino Acid Sequence; D001665:Binding Sites; D015195:Drug Design; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
D019428:HIV Integrase Inhibitors