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Molecules 2018, 23(8), 1858;

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

Chemical Biology Laboratory, Center of Cancer Research, Frederick, MD 21702, USA
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
College of Pharmacy and Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA
Department of Chemistry and Biochemistry, The University of Southern Mississippi, Hattiesburg, MS 39406, USA
Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO 80045, USA
Authors to whom correspondence should be addressed.
Academic Editor: Stefano Aquaro
Received: 25 June 2018 / Revised: 18 July 2018 / Accepted: 23 July 2018 / Published: 26 July 2018
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
Full-Text   |   PDF [1992 KB, uploaded 26 July 2018]   |  


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. View Full-Text
Keywords: HIV-1 integrase; viral protein R; photoaffinity probe; inhibitor HIV-1 integrase; viral protein R; photoaffinity probe; inhibitor

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Zhao, X.Z.; Métifiot, M.; Kiselev, E.; Kessl, J.J.; Maddali, K.; Marchand, C.; Kvaratskhelia, M.; Pommier, Y.; Burke, T.R., Jr. HIV-1 Integrase-Targeted Short Peptides Derived from a Viral Protein R Sequence. Molecules 2018, 23, 1858.

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