Advances in targeting nucleocapsid-nucleic acid interactions in HIV-1 therapy

Virus Res. 2014 Nov 26;193:135-43. doi: 10.1016/j.virusres.2014.07.004. Epub 2014 Jul 12.

Abstract

The continuing challenge of HIV-1 treatment resistance in patients creates a need for the development of new antiretroviral inhibitors. The HIV nucleocapsid (NC) protein is a potential therapeutic target. NC is necessary for viral RNA packaging and in the early stages of viral infection. The high level of NC amino acid conservation among all HIV-1 clades suggests a low tolerance for mutations. Thus, NC mutations that could arise during inhibitor treatment to provide resistance may render the virus less fit. Disruption of NC function provides a unique opportunity to strongly dampen replication at multiple points during the viral life cycle with a single inhibitor. Although NC exhibits desirable features for a potential antiviral target, the structural flexibility, size, and the presence of two zinc fingers makes small molecule targeting of NC a challenging task. In this review, we discuss the recent advances in strategies to develop inhibitors of NC function and present a perspective on potential novel approaches that may help to overcome some of the current challenges in the field.

Keywords: HIV-1; Inhibitors; Nucleocapsid protein; RNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Anti-HIV Agents / pharmacology
  • Anti-HIV Agents / therapeutic use*
  • HIV Infections / drug therapy*
  • HIV Infections / virology*
  • HIV-1 / physiology*
  • Humans
  • Nucleocapsid / chemistry
  • Nucleocapsid / metabolism*
  • Nucleocapsid Proteins / chemistry
  • Nucleocapsid Proteins / metabolism
  • Protein Binding / drug effects
  • RNA, Viral / chemistry
  • RNA, Viral / genetics
  • RNA, Viral / metabolism*
  • Zinc Fingers

Substances

  • Anti-HIV Agents
  • Nucleocapsid Proteins
  • RNA, Viral