A mimic of HIV-1 nucleocapsid protein impairs reverse transcription and displays antiviral activity

Abstract

Combined inhibition of HIV-1 reverse transcriptase and protease has significantly improved the treatment of AIDS. Nevertheless, resistance to these drugs occurs rapidly because of viral mutations, emphasizing the importance of identifying novel retroviral targets to develop new drug combinations. The critical role played by the nucleocapsid protein NCp7 of HIV-1 at different steps of the retrovirus life cycle makes it an attractive target for the development of new antiviral agents. NCp7 contains two highly conserved zinc fingers and is characterized by a three-dimensional structure that cannot be modified without a complete loss of infectivity of mutated viruses. Based on these structural data, we report that RB 2121, a cyclic peptide designed to mimic several essential biological determinants of NCp7, displays antiviral activity by inhibiting HIV-1 replication in CEM-4 cells infected by HIV-1. In vitro, RB 2121 does not interfere with HIV-1 cell entry and viral enzymes but is able to inhibit the annealing activities of NCp7 by recognizing nucleic acids. Analysis of proviral DNA synthesis by means of PCR has shown that RB 2121 acts at an early step of the retrovirus life cycle by inducing a dose-dependent reduction in transcribed DNA levels through inhibition of NCp7-reverse transcriptase interaction. Because of its original mechanism of action, RB 2121 provides an interesting lead for the rational development of new anti-HIV-1 agents that could be associated advantageously with enzyme inhibitors to counteract rapid virus mutations and resistance problems observed in tritherapies.