page_title: HIV ribosomal frameshift signal
section_title: As a potential therapeutic target
hierarchical_section_title: HIV ribosomal frameshift signal / As a potential therapeutic target
caption_attribution_description: English: An example of a lead therapeutic compound that targets the HIV-1 Ribosomal Frameshift Signal
context_page_description: HIV ribosomal frameshift signal is a ribosomal frameshift that human immunodeficiency virus uses to translate several different proteins from the same sequence.
  Intact and consistent protein biosynthesis relies on the ability of the ribosome to stay in the correct open reading frame during translation. When the ribosome fails to maintain the proper ORF, translation usually results in either incorrect protein synthesis or early termination as a result of the introduction of a premature stop codon. However, a shift in the ORF is not universally deleterious, as many viruses capitalize on this phenomenon by using a programmed ribosomal frameshift to translate several proteins from the same sequence, thereby maximizing the storage capacity of their genome. Thus, many viruses are categorized as having a polycistronic genome, meaning they employ multiple active ORF's in a single gene.
  The HIV-1 virus requires a programmed -1 ribosomal frameshift signal for the expression of the Pol gene, which is an example of a cis-acting element of gene regulation.
context_section_description: The HIV-1 ribosomal frameshift signal has emerged as a potential therapeutic target for the HIV-1 virus due to the requirement of the programmed ribosomal frameshift for the regulation of the Gag/Gag-Pol protein ratio and the relatively conserved structure.  Additionally, because the HIV-1 ribosomal frameshift signal relies on interactions between the viral mRNA and the host translational machinery, it is likely a more stable therapeutic target, because any selective pressure caused by a therapeutic compound would have to occur on the evolutionary time scale of the host instead of the rapidly evolving HIV-1 virus.  As a result, this may also reduce the risk of drug-resistant mutants experienced by other HIV-1 antiretroviral therapies.
  Recently (January 2014), the first therapeutic compound targeted at the HIV-1 ribosomal frameshift signal was reported by Ofori et al.  The lead compound was developed from a "hit" compound discovered through a resin-bound dynamic combinatorial library screen, and the structure is shown at right.  The EC50 values were reported to be 3.9uM for the Z conformation and 25.6uM for the E conformation.  The lead compound is symmetrical whereas the target downstream secondary RNA structure is non-symmetrical, suggesting that both supposed intercalators are necessary for high-affinity binding.  Using a dual-luciferase assay, they concluded that the compound functions by enhancing the frameshifting efficiency of the HIV-1 ribosomal frameshift signal, resulting in a decrease in the Gag/Gag-Pol protein ratio and thereby preventing the proper maturation of the viral particle and ultimately inhibiting infection.  Moving forward, structural studies of the interactions between the lead compound and the downstream secondary RNA structure of the HIV-1 ribosomal frameshift signal will be vital to understanding the reason for high affinity and the method of action.
caption: An example of a lead therapeutic compound that targets the HIV-1 Ribosomal Frameshift Signal
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