Important note: Information in this article was accurate in June 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, June 14 & 21, 1999
Daniel J. DeNoon, Senior Editor
CW HENDERSON PUBLISHER -- A novel anti-HIV drug works differently than other members of its class.
The compound, dubbed RB 2121, attacks the HIV-1 nucleocapsid (NC, or NCp7) protein. Unlike other NC inhibitors, which target NC's unique zinc "fingers," RB 2121 competes with NC for the recognition of its targets.
"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," wrote S. Druillennec of France's Institut National de la Sante et de la Recherche Medicale (INSERM) and Rhone-Poulenc-Rorer.
Druillennec et al. reported their findings in the Proceedings of the National Academy of Sciences ("A Mimic of HIV-1 Nucleocapsid Protein Impairs Reverse Transcription and Displays Antiviral Activity," Proc Natl Acad Sci U S A 1999 Apr 27;96(9):4886-91.
The HIV-1 NC protein is a major determinant of HIV infectivity. It has multiple actions crucial to the viral life cycle. These include protection of the genome against host-cell enzymes, packaging genomic RNA, and transformation of virus particles into their mature forms.
Druillennec et al. set out to create small molecules that mimic parts of the NC three-dimensional structure. They hoped that some of these molecules would successfully compete with the natural protein.
"Therefore, a simplified scaffold deduced from the NCp7 structure was developed with the main biological determinants of the protein introduced on a cyclic peptide, RB 2121, enabling them to adopt a relative spatial orientation close to that found in NCp7," they wrote.
In vitro studies showed that the compound acted as had been hoped, apparently by impairing formation of functional complexes of reverse transcriptase (RT), NCp7, and nucleic acid.
Other NC inhibitors currently under development force ejection of the zinc residues from the protein, making it inert. RB 2121 has a completely different mechanism of action.
An S-methylated cysteine derivative of RB 2121, dubbed RB 2124, also had anti-HIV activity but to a lesser extent than the parent compound.
"One difficulty of the approach could be the high concentration of NCp7 as compared with enzymes in the virus," Druillennec et al. acknowledged. "But the affinity of NCp7 for RT is relatively weak ... and most of these nucleocapsid molecules are bound to different nucleic acids present during the synthesis of the provirus."
The authors currently are working to improve the affinity and bioavailability of RB 2121 to obtain a drug suitable for clinical evaluation.
This work was supported by the French program against AIDS (Agence Nationale de Recherche sur le SIDA and SIDACTION).
The corresponding author for this study is B.P. Roques, Departement de Pharmacochimie Moleculaire Structurale, U 266 Institut National de la Sante d de la Recherche Medicale, Unite Mixte de Recherche, 8600 Centre National de la Recherche Scientifique, Unite de Formation et de Recherche des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75270 Paris, Cedex 06, France. Email: <roques@pharmacie.univ-paris5.fr>.
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