1. HIV-1 Integrase-Targeted Short Peptides Derived from a Viral Protein R Sequence.
- Author
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Zhao XZ, Métifiot M, Kiselev E, Kessl JJ, Maddali K, Marchand C, Kvaratskhelia M, Pommier Y, and Burke TR Jr
- Subjects
- Amino Acid Sequence, HIV Integrase Inhibitors chemical synthesis, HIV Integrase Inhibitors chemistry, Magnetic Resonance Spectroscopy, Models, Molecular, Peptides chemical synthesis, Peptides chemistry, Protein Binding, Protein Conformation, Protein Interaction Domains and Motifs, Protein Multimerization, Gene Products, vpr chemistry, Gene Products, vpr metabolism, HIV Infections virology, HIV Integrase metabolism, HIV Integrase Inhibitors pharmacology, HIV-1 physiology, Peptides pharmacology
- 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.
- Published
- 2018
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