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.