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.
Bibliographical noteFunding Information:
This study was supported by a starting grant from the European Research Council (ERC) (for AF), by a Nophar grant from the Chief Scientist, Ministry of Industry, Israel , with Johnson and Johnson (for AF and A. Loyter) and by the Israel Science Foundation (for A. Loyter). We thank Dr. Mario Lebendiker for his help with the gel filtration experiments.