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

  1. Author:
    Zhao, Xue Zhi [ORCID]
    Métifiot, Mathieu
    Kiselev, Evgeny
    Kessl, Jacques J [ORCID]
    Maddali, Kasthuraiah
    Marchand, Christophe
    Kvaratskhelia, Mamuka
    Pommier, Yves
    Burke, Terrence

  2. Author Address

    Chemical Biology Laboratory, Center of Cancer Research, Frederick, MD 21702, USA. Xuezhi.Zhao@nih.gov., Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. mathieu.metifiot@u-bordeaux.fr., 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@nih.gov., College of Pharmacy and Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA. Jacques.Kessl@usm.edu., Department of Chemistry and Biochemistry, The University of Southern Mississippi, Hattiesburg, MS 39406, USA. Jacques.Kessl@usm.edu., Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. maddalik@makorelabs.com., Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. marchanc@mail.nih.gov., College of Pharmacy and Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA. MAMUKA.KVARATSKHELIA@UCDENVER.EDU., Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO 80045, USA. MAMUKA.KVARATSKHELIA@UCDENVER.EDU., Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Yves.Pommier@nih.gov., Chemical Biology Laboratory, Center of Cancer Research, Frederick, MD 21702, USA. burkete@mail.nih.gov.,
    1. Year: 2018
    2. Date: Aug
    3. Epub Date: 2018 07 26
  2. Journal: Molecules
    1. 23
    2. 8
    3. Pages: pii: E1858
  4. Type of Article: Article
  5. Article Number: 1858
  6. ISSN: 1420-3049
  1. 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.

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External Sources

  1. View Full Text
  2. DOI: 10.3390/molecules23081858
  3. PMID: 30049955
  4. View record in Web of Science®
  5. WOS: 000445295500023
  6. PII : molecules23081858

Library Notes

  1. Fiscal Year: FY2017-2018
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