Discovery and Optimization of a Natural HIV-1 Entry Inhibitor Targeting the gp41 Fusion Peptide

Jan Münch; Ludger Ständker; Knut Adermann; Axel Schulz; Michael Schindler; Raghavan Chinnadurai; Stefan Pöhlmann; Chawaree Chaipan; Thorsten Biet; Thomas Peters; Bernd Meyer; Dennis Wilhelm; Hong Lu; Weiguo Jing; Shibo Jiang; Wolf Georg Forssmann; Frank Kirchhoff

doi:10.1016/j.cell.2007.02.042

Discovery and Optimization of a Natural HIV-1 Entry Inhibitor Targeting the gp41 Fusion Peptide

Jan Münch, Ludger Ständker, Knut Adermann, Axel Schulz, Michael Schindler, Raghavan Chinnadurai, Stefan Pöhlmann, Chawaree Chaipan, Thorsten Biet, Thomas Peters, Bernd Meyer, Dennis Wilhelm, Hong Lu, Weiguo Jing, Shibo Jiang, Wolf Georg Forssmann^*, Frank Kirchhoff

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Chemie und Metabolomics

246 Zitate (Scopus)

Abstract

A variety of molecules in human blood have been implicated in the inhibition of HIV-1. However, it remained elusive which circulating natural compounds are most effective in controlling viral replication in vivo. To identify natural HIV-1 inhibitors we screened a comprehensive peptide library generated from human hemofiltrate. The most potent fraction contained a 20-residue peptide, designated VIRUS-INHIBITORY PEPTIDE (VIRIP), corresponding to the C-proximal region of α1-antitrypsin, the most abundant circulating serine protease inhibitor. We found that VIRIP inhibits a wide variety of HIV-1 strains including those resistant to current antiretroviral drugs. Further analysis demonstrated that VIRIP blocks HIV-1 entry by interacting with the gp41 fusion peptide and showed that a few amino acid changes increase its antiretroviral potency by two orders of magnitude. Thus, as a highly specific natural inhibitor of the HIV-1 gp41 fusion peptide, VIRIP may lead to the development of another class of antiretroviral drugs.

Originalsprache	Englisch
Zeitschrift	Cell
Jahrgang	129
Ausgabenummer	2
Seiten (von - bis)	263-275
Seitenumfang	13
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2007.02.042
Publikationsstatus	Veröffentlicht - 20.04.2007

Fördermittel

We thank Bernhard Fleckenstein and Thomas Mertens for support; Veronica L. Kuhlemann, Ulrich Schubert, and Ingrid Bennett for critical reading of the manuscript; Ilka Uhrland, Jessika Babierowski, Nadja Auer, Nicola Bailer, Daniela Krnavek, and Louise Boyer-Chatenet for their excellent technical assistance; Alexander Steinkasserer and Jutta Eisemann for dendritic cells; Gerhard Rettinger, Herbert Riechelmann, Tilmann Keck, and Kai Johannes Lorenz for providing tonsils; Oliver Hartley for PSC-RANTES; Thomas Grunwald for his RSV studies; Harry John for bioanalytical support of VIRIP peptides; Peter Henklein for the synthesis of some fusion peptides; and Gabrielle Sass for helpful discussion. A number of reagents were obtained through the NIH AIDS Reagent Program. B.M. and T.P. acknowledge the grant (DFG ME1830/1) for the 700 MHz spectrometer. This work was supported by the government of Lower Saxony and by grants from the DFG and the Wilhelm-Sander Foundation and NIH grant 1R01AI067057-01A2 to F.K. W.-G.F. is founder and shareholder and L.S. is shareholder of Pharis Pharma Holding GmbH & Co. KG, the parent company of VIRO Pharmaceuticals GmbH & Co. KG. K.A. is Managing Scientific Director of VIRO Pharmaceuticals GmbH & Co. KG. The remaining authors have no financial interest related to this work.

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SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

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10.1016/j.cell.2007.02.042

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Münch, J., Ständker, L., Adermann, K., Schulz, A., Schindler, M., Chinnadurai, R., Pöhlmann, S., Chaipan, C., Biet, T., Peters, T., Meyer, B., Wilhelm, D., Lu, H., Jing, W., Jiang, S., Forssmann, W. G., & Kirchhoff, F. (2007). Discovery and Optimization of a Natural HIV-1 Entry Inhibitor Targeting the gp41 Fusion Peptide. Cell, 129(2), 263-275. https://doi.org/10.1016/j.cell.2007.02.042

@article{ad235c9e115042af801216a48b9732eb,

title = "Discovery and Optimization of a Natural HIV-1 Entry Inhibitor Targeting the gp41 Fusion Peptide",

abstract = "A variety of molecules in human blood have been implicated in the inhibition of HIV-1. However, it remained elusive which circulating natural compounds are most effective in controlling viral replication in vivo. To identify natural HIV-1 inhibitors we screened a comprehensive peptide library generated from human hemofiltrate. The most potent fraction contained a 20-residue peptide, designated VIRUS-INHIBITORY PEPTIDE (VIRIP), corresponding to the C-proximal region of α1-antitrypsin, the most abundant circulating serine protease inhibitor. We found that VIRIP inhibits a wide variety of HIV-1 strains including those resistant to current antiretroviral drugs. Further analysis demonstrated that VIRIP blocks HIV-1 entry by interacting with the gp41 fusion peptide and showed that a few amino acid changes increase its antiretroviral potency by two orders of magnitude. Thus, as a highly specific natural inhibitor of the HIV-1 gp41 fusion peptide, VIRIP may lead to the development of another class of antiretroviral drugs.",

author = "Jan M{\"u}nch and Ludger St{\"a}ndker and Knut Adermann and Axel Schulz and Michael Schindler and Raghavan Chinnadurai and Stefan P{\"o}hlmann and Chawaree Chaipan and Thorsten Biet and Thomas Peters and Bernd Meyer and Dennis Wilhelm and Hong Lu and Weiguo Jing and Shibo Jiang and Forssmann, \{Wolf Georg\} and Frank Kirchhoff",

note = "Funding Information: We thank Bernhard Fleckenstein and Thomas Mertens for support; Veronica L. Kuhlemann, Ulrich Schubert, and Ingrid Bennett for critical reading of the manuscript; Ilka Uhrland, Jessika Babierowski, Nadja Auer, Nicola Bailer, Daniela Krnavek, and Louise Boyer-Chatenet for their excellent technical assistance; Alexander Steinkasserer and Jutta Eisemann for dendritic cells; Gerhard Rettinger, Herbert Riechelmann, Tilmann Keck, and Kai Johannes Lorenz for providing tonsils; Oliver Hartley for PSC-RANTES; Thomas Grunwald for his RSV studies; Harry John for bioanalytical support of VIRIP peptides; Peter Henklein for the synthesis of some fusion peptides; and Gabrielle Sass for helpful discussion. A number of reagents were obtained through the NIH AIDS Reagent Program. B.M. and T.P. acknowledge the grant (DFG ME1830/1) for the 700 MHz spectrometer. This work was supported by the government of Lower Saxony and by grants from the DFG and the Wilhelm-Sander Foundation and NIH grant 1R01AI067057-01A2 to F.K. W.-G.F. is founder and shareholder and L.S. is shareholder of Pharis Pharma Holding GmbH \& Co. KG, the parent company of VIRO Pharmaceuticals GmbH \& Co. KG. K.A. is Managing Scientific Director of VIRO Pharmaceuticals GmbH \& Co. KG. The remaining authors have no financial interest related to this work. Copyright: Copyright 2009 Elsevier B.V., All rights reserved.",

year = "2007",

month = apr,

day = "20",

doi = "10.1016/j.cell.2007.02.042",

language = "English",

volume = "129",

pages = "263--275",

journal = "Cell",

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Münch, J, Ständker, L, Adermann, K, Schulz, A, Schindler, M, Chinnadurai, R, Pöhlmann, S, Chaipan, C, Biet, T , Peters, T, Meyer, B, Wilhelm, D, Lu, H, Jing, W, Jiang, S, Forssmann, WG & Kirchhoff, F 2007, 'Discovery and Optimization of a Natural HIV-1 Entry Inhibitor Targeting the gp41 Fusion Peptide', Cell, Jg. 129, Nr. 2, S. 263-275. https://doi.org/10.1016/j.cell.2007.02.042

TY - JOUR

T1 - Discovery and Optimization of a Natural HIV-1 Entry Inhibitor Targeting the gp41 Fusion Peptide

AU - Münch, Jan

AU - Ständker, Ludger

AU - Adermann, Knut

AU - Schulz, Axel

AU - Schindler, Michael

AU - Chinnadurai, Raghavan

AU - Pöhlmann, Stefan

AU - Chaipan, Chawaree

AU - Biet, Thorsten

AU - Peters, Thomas

AU - Meyer, Bernd

AU - Wilhelm, Dennis

AU - Lu, Hong

AU - Jing, Weiguo

AU - Jiang, Shibo

AU - Forssmann, Wolf Georg

AU - Kirchhoff, Frank

N1 - Funding Information: We thank Bernhard Fleckenstein and Thomas Mertens for support; Veronica L. Kuhlemann, Ulrich Schubert, and Ingrid Bennett for critical reading of the manuscript; Ilka Uhrland, Jessika Babierowski, Nadja Auer, Nicola Bailer, Daniela Krnavek, and Louise Boyer-Chatenet for their excellent technical assistance; Alexander Steinkasserer and Jutta Eisemann for dendritic cells; Gerhard Rettinger, Herbert Riechelmann, Tilmann Keck, and Kai Johannes Lorenz for providing tonsils; Oliver Hartley for PSC-RANTES; Thomas Grunwald for his RSV studies; Harry John for bioanalytical support of VIRIP peptides; Peter Henklein for the synthesis of some fusion peptides; and Gabrielle Sass for helpful discussion. A number of reagents were obtained through the NIH AIDS Reagent Program. B.M. and T.P. acknowledge the grant (DFG ME1830/1) for the 700 MHz spectrometer. This work was supported by the government of Lower Saxony and by grants from the DFG and the Wilhelm-Sander Foundation and NIH grant 1R01AI067057-01A2 to F.K. W.-G.F. is founder and shareholder and L.S. is shareholder of Pharis Pharma Holding GmbH & Co. KG, the parent company of VIRO Pharmaceuticals GmbH & Co. KG. K.A. is Managing Scientific Director of VIRO Pharmaceuticals GmbH & Co. KG. The remaining authors have no financial interest related to this work. Copyright: Copyright 2009 Elsevier B.V., All rights reserved.

PY - 2007/4/20

Y1 - 2007/4/20

N2 - A variety of molecules in human blood have been implicated in the inhibition of HIV-1. However, it remained elusive which circulating natural compounds are most effective in controlling viral replication in vivo. To identify natural HIV-1 inhibitors we screened a comprehensive peptide library generated from human hemofiltrate. The most potent fraction contained a 20-residue peptide, designated VIRUS-INHIBITORY PEPTIDE (VIRIP), corresponding to the C-proximal region of α1-antitrypsin, the most abundant circulating serine protease inhibitor. We found that VIRIP inhibits a wide variety of HIV-1 strains including those resistant to current antiretroviral drugs. Further analysis demonstrated that VIRIP blocks HIV-1 entry by interacting with the gp41 fusion peptide and showed that a few amino acid changes increase its antiretroviral potency by two orders of magnitude. Thus, as a highly specific natural inhibitor of the HIV-1 gp41 fusion peptide, VIRIP may lead to the development of another class of antiretroviral drugs.

AB - A variety of molecules in human blood have been implicated in the inhibition of HIV-1. However, it remained elusive which circulating natural compounds are most effective in controlling viral replication in vivo. To identify natural HIV-1 inhibitors we screened a comprehensive peptide library generated from human hemofiltrate. The most potent fraction contained a 20-residue peptide, designated VIRUS-INHIBITORY PEPTIDE (VIRIP), corresponding to the C-proximal region of α1-antitrypsin, the most abundant circulating serine protease inhibitor. We found that VIRIP inhibits a wide variety of HIV-1 strains including those resistant to current antiretroviral drugs. Further analysis demonstrated that VIRIP blocks HIV-1 entry by interacting with the gp41 fusion peptide and showed that a few amino acid changes increase its antiretroviral potency by two orders of magnitude. Thus, as a highly specific natural inhibitor of the HIV-1 gp41 fusion peptide, VIRIP may lead to the development of another class of antiretroviral drugs.

UR - https://www.scopus.com/pages/publications/34147137981

U2 - 10.1016/j.cell.2007.02.042

DO - 10.1016/j.cell.2007.02.042

M3 - Journal articles

C2 - 17448989

AN - SCOPUS:34147137981

SN - 0092-8674

VL - 129

SP - 263

EP - 275

JO - Cell

JF - Cell

IS - 2

ER -

Discovery and Optimization of a Natural HIV-1 Entry Inhibitor Targeting the gp41 Fusion Peptide

Abstract

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