title: A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry.
abstract: Binding to the primary receptor, CD4, triggers conformational changes in the metastable HIV-1 envelope glycoprotein (Env) trimer ((gp120-gp41)3) that are important for virus entry into host cells. These changes include an 'opening' of the trimer, creation of a binding site for the CCR5 co-receptor and formation and/or exposure of a gp41 coiled coil. Here we identify a new compound, 18A (1), that specifically inhibits the entry of a wide range of HIV-1 isolates. 18A does not interfere with CD4 or CCR5 binding, but it inhibits the CD4-induced disruption of quaternary structures at the trimer apex and the exposure of the gp41 HR1 coiled coil. Analysis of HIV-1 variants with increased or reduced sensitivity to 18A suggests that the inhibitor can distinguish distinct conformational states of gp120 in the unliganded Env trimer. The broad-range activity and observed hypersensitivity of resistant mutants to antibody neutralization support further investigation of 18A.
authors.affiliation: 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alon
authors.initials: A
authors.lastname: Herschhorn
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gu
authors.affiliation: 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Espy
authors.affiliation: 1] Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montreal, Quebec, Canada. [2] Department of Microbiology, Infectiology and Immunology ,Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Richard
authors.affiliation: 1] Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montreal, Quebec, Canada. [2] Department of Microbiology, Infectiology and Immunology ,Université de Montréal, Montreal, Quebec, Canada. [3] Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
authors.affiliation: 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Sodroski
mesh_terms: D015704:CD4 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary / Q000187:drug effects*; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012664:Semicarbazones / Q000737:chemistry / Q000494:pharmacology*; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*; D019562:Viral Load / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: C000595197:1-(2,1,3-benzothiadiazol-4-yl)-3-((E)-(4-hydroxyphenyl)methyleneamino)urea; C584933:CCR5 protein, human; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D011993:Recombinant Fusion Proteins; D012664:Semicarbazones; D013830:Thiadiazoles; C514793:gp120 protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1