The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement.

Nef is a multifunctional HIV-1 protein that accelerates progression to AIDS, and enhances the infectivity of progeny viruses through a mechanism that is not yet understood. Here, we show that the small molecule compound 2c reduces Nef-mediated viral infectivity enhancement. When added to viral produ...

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Autores principales: Nopporn Chutiwitoonchai, Masateru Hiyoshi, Philip Mwimanzi, Takamasa Ueno, Akio Adachi, Hirotaka Ode, Hironori Sato, Oliver T Fackler, Seiji Okada, Shinya Suzu
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Publicado: Public Library of Science (PLoS) 2011
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spelling oai:doaj.org-article:6edaba99480b4faaa96bd8138c571c9b2021-11-18T07:34:17ZThe identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement.1932-620310.1371/journal.pone.0027696https://doaj.org/article/6edaba99480b4faaa96bd8138c571c9b2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22110726/?tool=EBIhttps://doaj.org/toc/1932-6203Nef is a multifunctional HIV-1 protein that accelerates progression to AIDS, and enhances the infectivity of progeny viruses through a mechanism that is not yet understood. Here, we show that the small molecule compound 2c reduces Nef-mediated viral infectivity enhancement. When added to viral producer cells, 2c did not affect the efficiency of viral production itself. However, the infectivity of the viruses produced in the presence of 2c was significantly lower than that of control viruses. Importantly, an inhibitory effect was observed with Nef(+) wild-type viruses, but not with viruses produced in the absence of Nef or in the presence of proline-rich PxxP motif-disrupted Nef, both of which displayed significantly reduced intrinsic infectivity. Meanwhile, the overexpression of the SH3 domain of the tyrosine kinase Hck, which binds to a PxxP motif in Nef, also reduced viral infectivity. Importantly, 2c inhibited Hck SH3-Nef binding, which was more marked when Nef was pre-incubated with 2c prior to its incubation with Hck, indicating that both Hck SH3 and 2c directly bind to Nef and that their binding sites overlap. These results imply that both 2c and the Hck SH3 domain inhibit the interaction of Nef with an unidentified host protein and thereby reduce Nef-mediated infectivity enhancement. The first inhibitory compound 2c is therefore a valuable chemical probe for revealing the underlying molecular mechanism by which Nef enhances the infectivity of HIV-1.Nopporn ChutiwitoonchaiMasateru HiyoshiPhilip MwimanziTakamasa UenoAkio AdachiHirotaka OdeHironori SatoOliver T FacklerSeiji OkadaShinya SuzuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 11, p e27696 (2011)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Nopporn Chutiwitoonchai
Masateru Hiyoshi
Philip Mwimanzi
Takamasa Ueno
Akio Adachi
Hirotaka Ode
Hironori Sato
Oliver T Fackler
Seiji Okada
Shinya Suzu
The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement.
description Nef is a multifunctional HIV-1 protein that accelerates progression to AIDS, and enhances the infectivity of progeny viruses through a mechanism that is not yet understood. Here, we show that the small molecule compound 2c reduces Nef-mediated viral infectivity enhancement. When added to viral producer cells, 2c did not affect the efficiency of viral production itself. However, the infectivity of the viruses produced in the presence of 2c was significantly lower than that of control viruses. Importantly, an inhibitory effect was observed with Nef(+) wild-type viruses, but not with viruses produced in the absence of Nef or in the presence of proline-rich PxxP motif-disrupted Nef, both of which displayed significantly reduced intrinsic infectivity. Meanwhile, the overexpression of the SH3 domain of the tyrosine kinase Hck, which binds to a PxxP motif in Nef, also reduced viral infectivity. Importantly, 2c inhibited Hck SH3-Nef binding, which was more marked when Nef was pre-incubated with 2c prior to its incubation with Hck, indicating that both Hck SH3 and 2c directly bind to Nef and that their binding sites overlap. These results imply that both 2c and the Hck SH3 domain inhibit the interaction of Nef with an unidentified host protein and thereby reduce Nef-mediated infectivity enhancement. The first inhibitory compound 2c is therefore a valuable chemical probe for revealing the underlying molecular mechanism by which Nef enhances the infectivity of HIV-1.
format article
author Nopporn Chutiwitoonchai
Masateru Hiyoshi
Philip Mwimanzi
Takamasa Ueno
Akio Adachi
Hirotaka Ode
Hironori Sato
Oliver T Fackler
Seiji Okada
Shinya Suzu
author_facet Nopporn Chutiwitoonchai
Masateru Hiyoshi
Philip Mwimanzi
Takamasa Ueno
Akio Adachi
Hirotaka Ode
Hironori Sato
Oliver T Fackler
Seiji Okada
Shinya Suzu
author_sort Nopporn Chutiwitoonchai
title The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement.
title_short The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement.
title_full The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement.
title_fullStr The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement.
title_full_unstemmed The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement.
title_sort identification of a small molecule compound that reduces hiv-1 nef-mediated viral infectivity enhancement.
publisher Public Library of Science (PLoS)
publishDate 2011
url https://doaj.org/article/6edaba99480b4faaa96bd8138c571c9b
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