The Nucleocapsid Protein of HIV-1 as a Promising Therapeutic Target for Antiviral Drugs

Abstract

The nucleocapsid protein (NCp7) is a major HIV-1 structural protein that plays key roles in viral replication, mainly through its conserved zinc fingers that direct specific interactions with the viral nucleic acids. Owing to its high degree of conservation and critical functions, NCp7 represents a target of choice for drugs that can potentially complement HAART, thus possibly impairing the circulation of drug-resistant HIV-1 strains. Zinc ejectors showing potent antiretroviral activity were developed, but early generations suffered from limited selectively and significant toxicity. Compounds with improved selectivity have been developed and are being explored as topical microbicide candidates. Several classes of molecules inhibiting the interaction of NCp7 with the viral nucleic acids have also been developed. Although small molecules would be more suited for drug development, most molecules selected by screening showed limited antiretroviral activity. Peptides and RNA aptamers appear to be more promising, but the mechanism of their antiretroviral activity remains elusive. Substantial and more concerted efforts are needed to further develop anti-HIV drugs targeting NCp7 and bring them to the clinic.