Abstract
HIV-1 integrase (IN) inhibitors represent a new class of highly effective anti-AIDS therapeutics. Current FDA-approved IN strand transfer inhibitors (INSTIs) share a common mechanism of action that involves chelation of catalytic divalent metal ions. However, the emergence of IN mutants having reduced sensitivity to these inhibitors underlies efforts to derive agents that antagonize IN function by alternate mechanisms. Integrase along with the 96-residue multifunctional accessory protein, viral protein R (Vpr), are both components of the HIV-1 pre-integration complex (PIC). Coordinated interactions within the PIC are important for viral replication. Herein, we report a 7-mer peptide based on the shortened Vpr (69–75) sequence containing a biotin group and a photo-reactive benzoylphenylalanyl residue, and which exhibits low micromolar IN inhibitory potency. Photo-crosslinking experiments have indicated that the peptide directly binds IN. The peptide does not interfere with IN-DNA interactions or induce higher-order, aberrant IN multimerization, suggesting a mode of action for the peptide that is distinct from clinically used INSTIs and developmental allosteric IN inhibitors. This compact Vpr-derived peptide may serve as a valuable pharmacological tool to identify a potential new pharmacologic site.
Highlights
HIV-1 integrase (IN) is a virally encoded polynucleotidyl transferase that inserts reverse-transcribed viral cDNA into the host genome using two sequential reactions, cleavage of the30 -dinucleotides from viral DNA, referred to as 30 -processing (30 -P), and insertion of the processed ends of viral DNA into the host genome, termed strand transfer (ST) [1]
We found that the shortened sequence can exhibit low micromolar inhibitory potency
viral protein R (Vpr)-derived peptides have previously been shown to inhibit IN function in in vitro assays
Summary
HIV-1 integrase (IN) is a virally encoded polynucleotidyl transferase that inserts reverse-transcribed viral cDNA into the host genome using two sequential reactions, cleavage of the. As Vpr its complex and not completely understood of HIV-1 inpathogensis non-dividing cells, itinpotentially affords and alternate targetnonfor role in the of HIV-1 non-dividing cells, ait new potentially affords anon-catalytic new and alternate therapeutic exploration [13,14,15,16,17,18]. ST-inhibitory as being shared by pooled 15-mer Vpr-derived peptides. To conformations of conformations the Vpr (58–75)-derived “EAIIRILQQLL [24] These structural stabilize α-helix of the Vprsequence,. Vpr-derived peptides to inhibit in within a cellular context [18]. The ability of Vpr-derived peptides to inhibit IN in in vitroin vitro assays may reflect binding on IN thatbemay be unrelated to thefunctions other functions in assays may reflect binding to sitestoonsites. IN thatbinding are important that are important forofpeptide [25]. for peptide binding [25]
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