Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370

Zvi Hayouka; Aviad Levin; Michal Maes; Eran Hadas; Deborah E. Shalev; David J. Volsky; Abraham Loyter; Assaf Friedler

doi:10.1016/j.bbrc.2010.02.100

Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370

Zvi Hayouka, Aviad Levin, Michal Maes, Eran Hadas, Deborah E. Shalev, David J. Volsky, Abraham Loyter, Assaf Friedler^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

The HIV-1 integrase protein (IN) mediates integration of the viral cDNA into the host genome and is a target for anti-HIV drugs. We have recently described a peptide derived from residues 361-370 of the IN cellular partner protein LEDGF/p75, which inhibited IN catalytic activity in vitro and HIV-1 replication in cells. Here we performed a comprehensive study of the LEDGF 361-370 mechanism of action in vitro, in cells and in vivo. Alanine scan, fluorescence anisotropy binding studies, homology modeling and NMR studies demonstrated that all residues in LEDGF 361-370 contribute to IN binding and inhibition. Kinetic studies in cells showed that LEDGF 361-370 specifically inhibited integration of viral cDNA. Thus, the full peptide was chosen for in vivo studies, in which it inhibited the production of HIV-1 RNA in mouse model. We conclude that the full LEDGF 361-370 peptide is a potent HIV-1 inhibitor and may be used for further development as an anti-HIV lead compound.

Original language	English
Pages (from-to)	260-265
Number of pages	6
Journal	Biochemical and Biophysical Research Communications
Volume	394
Issue number	2
DOIs	https://doi.org/10.1016/j.bbrc.2010.02.100
State	Published - 2 Apr 2010

Bibliographical note

Funding Information:
This study was supported by a starting grant from the European Research Council (ERC) (to A.F.) and by Grants DA017618 and NS054580 from the National Institutes of Health, the US Public Health Service (to D.J.V.). We would like to thank G. Bentsman and D. Kim for technical help in animal experiments.

Keywords

Alanine scan
Fluorescence anisotropy
HIV-1
Homology modeling
Integrase
LEDGF/p75
NMR
Peptides

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbrc.2010.02.100

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title = "Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370",

abstract = "The HIV-1 integrase protein (IN) mediates integration of the viral cDNA into the host genome and is a target for anti-HIV drugs. We have recently described a peptide derived from residues 361-370 of the IN cellular partner protein LEDGF/p75, which inhibited IN catalytic activity in vitro and HIV-1 replication in cells. Here we performed a comprehensive study of the LEDGF 361-370 mechanism of action in vitro, in cells and in vivo. Alanine scan, fluorescence anisotropy binding studies, homology modeling and NMR studies demonstrated that all residues in LEDGF 361-370 contribute to IN binding and inhibition. Kinetic studies in cells showed that LEDGF 361-370 specifically inhibited integration of viral cDNA. Thus, the full peptide was chosen for in vivo studies, in which it inhibited the production of HIV-1 RNA in mouse model. We conclude that the full LEDGF 361-370 peptide is a potent HIV-1 inhibitor and may be used for further development as an anti-HIV lead compound.",

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author = "Zvi Hayouka and Aviad Levin and Michal Maes and Eran Hadas and Shalev, {Deborah E.} and Volsky, {David J.} and Abraham Loyter and Assaf Friedler",

note = "Funding Information: This study was supported by a starting grant from the European Research Council (ERC) (to A.F.) and by Grants DA017618 and NS054580 from the National Institutes of Health, the US Public Health Service (to D.J.V.). We would like to thank G. Bentsman and D. Kim for technical help in animal experiments.",

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AU - Shalev, Deborah E.

AU - Volsky, David J.

AU - Loyter, Abraham

AU - Friedler, Assaf

N1 - Funding Information: This study was supported by a starting grant from the European Research Council (ERC) (to A.F.) and by Grants DA017618 and NS054580 from the National Institutes of Health, the US Public Health Service (to D.J.V.). We would like to thank G. Bentsman and D. Kim for technical help in animal experiments.

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N2 - The HIV-1 integrase protein (IN) mediates integration of the viral cDNA into the host genome and is a target for anti-HIV drugs. We have recently described a peptide derived from residues 361-370 of the IN cellular partner protein LEDGF/p75, which inhibited IN catalytic activity in vitro and HIV-1 replication in cells. Here we performed a comprehensive study of the LEDGF 361-370 mechanism of action in vitro, in cells and in vivo. Alanine scan, fluorescence anisotropy binding studies, homology modeling and NMR studies demonstrated that all residues in LEDGF 361-370 contribute to IN binding and inhibition. Kinetic studies in cells showed that LEDGF 361-370 specifically inhibited integration of viral cDNA. Thus, the full peptide was chosen for in vivo studies, in which it inhibited the production of HIV-1 RNA in mouse model. We conclude that the full LEDGF 361-370 peptide is a potent HIV-1 inhibitor and may be used for further development as an anti-HIV lead compound.

AB - The HIV-1 integrase protein (IN) mediates integration of the viral cDNA into the host genome and is a target for anti-HIV drugs. We have recently described a peptide derived from residues 361-370 of the IN cellular partner protein LEDGF/p75, which inhibited IN catalytic activity in vitro and HIV-1 replication in cells. Here we performed a comprehensive study of the LEDGF 361-370 mechanism of action in vitro, in cells and in vivo. Alanine scan, fluorescence anisotropy binding studies, homology modeling and NMR studies demonstrated that all residues in LEDGF 361-370 contribute to IN binding and inhibition. Kinetic studies in cells showed that LEDGF 361-370 specifically inhibited integration of viral cDNA. Thus, the full peptide was chosen for in vivo studies, in which it inhibited the production of HIV-1 RNA in mouse model. We conclude that the full LEDGF 361-370 peptide is a potent HIV-1 inhibitor and may be used for further development as an anti-HIV lead compound.

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Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370

Abstract

Bibliographical note

Keywords

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