title: The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement.
abstract: 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.
authors: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors: Nopporn
authors: N
authors: Chutiwitoonchai
authors: Masateru
authors: M
authors: Hiyoshi
authors: Philip
authors: P
authors: Mwimanzi
authors: Takamasa
authors: T
authors: Ueno
authors: Akio
authors: A
authors: Adachi
authors: Hirotaka
authors: H
authors: Ode
authors: Hironori
authors: H
authors: Sato
authors: Oliver T
authors: OT
authors: Fackler
authors: Seiji
authors: S
authors: Okada
authors: Shinya
authors: S
authors: Suzu
mesh_terms: D020816:Amino Acid Motifs; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D008958:Models, Molecular; D011392:Proline; D051572:Proto-Oncogene Proteins c-hck / Q000737:chemistry / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D019380:Anti-HIV Agents; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D011392:Proline; D051572:Proto-Oncogene Proteins c-hck