title: Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition.
abstract: The optimization, based on computational, thermodynamic, and crystallographic data, of a series of small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120 of human immunodeficiency virus (HIV) has been achieved. Importantly, biological evaluation revealed that the small-molecule CD4 mimics (4-7) inhibit HIV-1 entry into target cells with both significantly higher potency and neutralization breadth than previous congeners, while maintaining high selectivity for the target virus. Their binding mode was characterized via thermodynamic and crystallographic studies.
authors.affiliation: Department of Chemistry, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Bruno
authors.initials: B
authors.lastname: Melillo
authors.affiliation: Department of Biochemistry and Molecular Biophysics and Department of Physiology and Cellular Biophysics, Columbia University , New York, New York 10032, United States.
authors.forename: Shuaiyi
authors.initials: S
authors.lastname: Liang
authors.affiliation: Department of Chemistry, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Jongwoo
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Biology, The Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Arne
authors.initials: A
authors.lastname: Schön
authors.affiliation: Department of Chemistry, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Courter
authors.affiliation: Department of Chemistry, Bryn Mawr College , Bryn Mawr, Pennsylvania 19010, United States.
authors.forename: Judith M
authors.initials: JM
authors.lastname: LaLonde
authors.affiliation: Department of Chemistry, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wendler
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, and Department of Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Princiotto
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, and Department of Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.affiliation: Department of Biology, The Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, United States; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, United States; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, and Department of Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.affiliation: Department of Biochemistry and Molecular Biophysics and Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, United States; Department of Biochemistry and Molecular Biophysics and Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, United States.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Hendrickson
authors.affiliation: Department of Chemistry, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
keywords: CD4; HIV; X-ray crystallography; entry inhibitor; gp120; protein−protein interactions; structure-based drug design; thermodynamics; viral inhibition