HIV-1 Integrase-Targeted Short Peptides Derived from a Viral Protein R Sequence
Xue Zhi Zhao,
Mathieu Métifiot,
Evgeny Kiselev,
Jacques J. Kessl,
Kasthuraiah Maddali,
Christophe Marchand,
Mamuka Kvaratskhelia,
Yves Pommier,
Terrence R. Burke
Affiliations
Xue Zhi Zhao
Chemical Biology Laboratory, Center of Cancer Research, Frederick, MD 21702, USA
Mathieu Métifiot
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Evgeny Kiselev
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Jacques J. Kessl
College of Pharmacy and Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA
Kasthuraiah Maddali
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Christophe Marchand
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Mamuka Kvaratskhelia
College of Pharmacy and Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA
Yves Pommier
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Terrence R. Burke
Chemical Biology Laboratory, Center of Cancer Research, Frederick, MD 21702, USA
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.
