A specific protein disorder catalyzer of HIV-1 Nef

Adrien Lugari; Sebastian Breuer; Thibault Coursindel; Sandrine Opi; Audrey Restouin; Xiaoli Shi; Alexis Nazabal; Bruce E. Torbett; Jean Martinez; Yves Collette; Isabelle Parrot; Stefan T. Arold; Xavier Morelli

doi:10.1016/j.bmc.2011.10.051

A specific protein disorder catalyzer of HIV-1 Nef

Adrien Lugari, Sebastian Breuer, Thibault Coursindel, Sandrine Opi, Audrey Restouin, Xiaoli Shi, Alexis Nazabal, Bruce E. Torbett, Jean Martinez, Yves Collette, Isabelle Parrot, Stefan T. Arold^*, Xavier Morelli

^*Corresponding author for this work

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

5 Scopus citations

Abstract

The HIV-1 auxiliary protein Nef is required for the onset and progression of AIDS in HIV-1-infected persons. Here, we have deciphered the mode of action of a second-generation inhibitor of Nef, DLC27-14, presenting a competitive IC ₅₀ of ∼16 μM measured by MALDI-TOF experiments. Thermal protein denaturation experiments revealed a negative effect on stability of Nef in the presence of a saturating concentration of the inhibitor. The destabilizing action of DLC27-14 was confirmed by a HIV protease-based experiment, in which the protease sensitivity of DLC27-14-bound Nef was three times as high as that of apo Nef. The only compatible docking modes of action for DLC27-14 suggest that DLC27-14 promotes an opening of two α-helices that would destabilize the Nef core domain. DLC27-14 thus acts as a specific protein disorder catalyzer that destabilizes the folded conformation of the protein. Our results open novel avenues toward the development of next-generation Nef inhibitors.

Original language	English (US)
Pages (from-to)	7401-7406
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry
Volume	19
Issue number	24
DOIs	https://doi.org/10.1016/j.bmc.2011.10.051
State	Published - Dec 15 2011
Externally published	Yes

Bibliographical note

Funding Information:
The project was supported by the ANRS (Agence Nationale de Recherche sur le SIDA et les Hépatites Virales) and the CNRS (Centre National de la Recherche Scientifique). This research is supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant (CA016672). A.L. and S.O. were supported by a fellowship from the ANRS. T.C. was supported by a fellowship from the MESR (Ministère de l’Enseignement Superieur et de la Recherche). X.S. was supported by a fellowship from the French Embassy in China. S.B. was supported by CHRP-F09-SRI-205. We are grateful to Dr. I. Engels and S. Espinola for providing valuable technical expertise with the DSLS-based thermal protein denaturation at the Genomics Institute of the Novartis Research Foundation. We also would like to greatly thank K. Muller for editorial assistance.

Keywords

HIV-1 Nef inhibitor
Mass spectrometry
Molecular modeling
Protein-protein interaction inhibitor
Thermostability

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

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

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10.1016/j.bmc.2011.10.051

Cite this

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title = "A specific protein disorder catalyzer of HIV-1 Nef",

abstract = "The HIV-1 auxiliary protein Nef is required for the onset and progression of AIDS in HIV-1-infected persons. Here, we have deciphered the mode of action of a second-generation inhibitor of Nef, DLC27-14, presenting a competitive IC 50 of ∼16 μM measured by MALDI-TOF experiments. Thermal protein denaturation experiments revealed a negative effect on stability of Nef in the presence of a saturating concentration of the inhibitor. The destabilizing action of DLC27-14 was confirmed by a HIV protease-based experiment, in which the protease sensitivity of DLC27-14-bound Nef was three times as high as that of apo Nef. The only compatible docking modes of action for DLC27-14 suggest that DLC27-14 promotes an opening of two α-helices that would destabilize the Nef core domain. DLC27-14 thus acts as a specific protein disorder catalyzer that destabilizes the folded conformation of the protein. Our results open novel avenues toward the development of next-generation Nef inhibitors.",

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author = "Adrien Lugari and Sebastian Breuer and Thibault Coursindel and Sandrine Opi and Audrey Restouin and Xiaoli Shi and Alexis Nazabal and Torbett, {Bruce E.} and Jean Martinez and Yves Collette and Isabelle Parrot and Arold, {Stefan T.} and Xavier Morelli",

note = "Funding Information: The project was supported by the ANRS (Agence Nationale de Recherche sur le SIDA et les H{\'e}patites Virales) and the CNRS (Centre National de la Recherche Scientifique). This research is supported in part by the National Institutes of Health through MD Anderson{\textquoteright}s Cancer Center Support Grant (CA016672). A.L. and S.O. were supported by a fellowship from the ANRS. T.C. was supported by a fellowship from the MESR (Minist{\`e}re de l{\textquoteright}Enseignement Superieur et de la Recherche). X.S. was supported by a fellowship from the French Embassy in China. S.B. was supported by CHRP-F09-SRI-205. We are grateful to Dr. I. Engels and S. Espinola for providing valuable technical expertise with the DSLS-based thermal protein denaturation at the Genomics Institute of the Novartis Research Foundation. We also would like to greatly thank K. Muller for editorial assistance. ",

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AU - Breuer, Sebastian

AU - Coursindel, Thibault

AU - Opi, Sandrine

AU - Restouin, Audrey

AU - Shi, Xiaoli

AU - Nazabal, Alexis

AU - Torbett, Bruce E.

AU - Martinez, Jean

AU - Collette, Yves

AU - Parrot, Isabelle

AU - Arold, Stefan T.

AU - Morelli, Xavier

N1 - Funding Information: The project was supported by the ANRS (Agence Nationale de Recherche sur le SIDA et les Hépatites Virales) and the CNRS (Centre National de la Recherche Scientifique). This research is supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant (CA016672). A.L. and S.O. were supported by a fellowship from the ANRS. T.C. was supported by a fellowship from the MESR (Ministère de l’Enseignement Superieur et de la Recherche). X.S. was supported by a fellowship from the French Embassy in China. S.B. was supported by CHRP-F09-SRI-205. We are grateful to Dr. I. Engels and S. Espinola for providing valuable technical expertise with the DSLS-based thermal protein denaturation at the Genomics Institute of the Novartis Research Foundation. We also would like to greatly thank K. Muller for editorial assistance.

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N2 - The HIV-1 auxiliary protein Nef is required for the onset and progression of AIDS in HIV-1-infected persons. Here, we have deciphered the mode of action of a second-generation inhibitor of Nef, DLC27-14, presenting a competitive IC 50 of ∼16 μM measured by MALDI-TOF experiments. Thermal protein denaturation experiments revealed a negative effect on stability of Nef in the presence of a saturating concentration of the inhibitor. The destabilizing action of DLC27-14 was confirmed by a HIV protease-based experiment, in which the protease sensitivity of DLC27-14-bound Nef was three times as high as that of apo Nef. The only compatible docking modes of action for DLC27-14 suggest that DLC27-14 promotes an opening of two α-helices that would destabilize the Nef core domain. DLC27-14 thus acts as a specific protein disorder catalyzer that destabilizes the folded conformation of the protein. Our results open novel avenues toward the development of next-generation Nef inhibitors.

AB - The HIV-1 auxiliary protein Nef is required for the onset and progression of AIDS in HIV-1-infected persons. Here, we have deciphered the mode of action of a second-generation inhibitor of Nef, DLC27-14, presenting a competitive IC 50 of ∼16 μM measured by MALDI-TOF experiments. Thermal protein denaturation experiments revealed a negative effect on stability of Nef in the presence of a saturating concentration of the inhibitor. The destabilizing action of DLC27-14 was confirmed by a HIV protease-based experiment, in which the protease sensitivity of DLC27-14-bound Nef was three times as high as that of apo Nef. The only compatible docking modes of action for DLC27-14 suggest that DLC27-14 promotes an opening of two α-helices that would destabilize the Nef core domain. DLC27-14 thus acts as a specific protein disorder catalyzer that destabilizes the folded conformation of the protein. Our results open novel avenues toward the development of next-generation Nef inhibitors.

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KW - Mass spectrometry

KW - Molecular modeling

KW - Protein-protein interaction inhibitor

KW - Thermostability

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ER -

A specific protein disorder catalyzer of HIV-1 Nef

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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