HIV-1 Integrase-Targeted Short Peptides Derived from a Viral Protein R Sequence

• Published in: Molecules (Basel, Switzerland) Vol. 23; no. 8; p. 1858
• Main Authors: Zhao, Xue Zhi, Métifiot, Mathieu, Kiselev, Evgeny, Kessl, Jacques J, Maddali, Kasthuraiah, Marchand, Christophe, Kvaratskhelia, Mamuka, Pommier, Yves, Burke, Jr, Terrence R
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.07.2018; MDPI
• Subjects: Acquired immune deficiency syndrome; AIDS; Allosteric properties; Amino Acid Sequence; Biotin; Chelation; Crosslinking; Deoxyribonucleic acid; DNA; Gene Products, vpr - chemistry; Gene Products, vpr - metabolism; HIV Infections - virology; HIV Integrase - metabolism; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV-1 - physiology; HIV-1 integrase; inhibitor; Inhibitors; Integrase; Life Sciences; Magnetic Resonance Spectroscopy; Metal ions; Microbiology and Parasitology; Mode of action; Models, Molecular; Mutants; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Pharmacology; photoaffinity probe; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Protein Multimerization; Proteins; viral protein R; Virology; Vpr protein; photoaffinity probe; inhibitor; HIV-1 integrase; viral protein R
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules23081858

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.