Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein

In this study we present the use of 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). Shown is the NMR solution structure ensemble of c(MZ 4-1), the most active LEDGF 361-370-derived cyclic peptide, in the presence of IN. The backbone RMSD for the final ensemble of structures of the unbound c(MZ 4-1) was 1.74 Å, and the local RMSD for residues 366-369 (sticks) was 0.46 Å. In the presence of IN the local RMSD of the same region decreased to 0.04 Å (sticks) while the rest of the cyclic peptide is flexible. Our results indicate that this cyclic peptide, when coupled with FDA-approved drugs, may show combined improved anti-HIV activity. c(MZ 4-1) mimics the bioactive conformation of LEDGF/p75 361-370.