title: Small-molecule CD4 mimics interact with a highly conserved pocket on HIV-1 gp120.
abstract: Human immunodeficiency virus (HIV-1) interaction with the primary receptor, CD4, induces conformational changes in the viral envelope glycoproteins that allow binding to the CCR5 second receptor and virus entry into the host cell. The small molecule NBD-556 mimics CD4 by binding the gp120 exterior envelope glycoprotein, moderately inhibiting virus entry into CD4-expressing target cells and enhancing CCR5 binding and virus entry into CCR5-expressing cells lacking CD4. Studies of NBD-556 analogs and gp120 mutants suggest that (1) NBD-556 binds within the Phe 43 cavity, a highly conserved, functionally important pocket formed as gp120 assumes the CD4-bound conformation; (2) the NBD-556 phenyl ring projects into the Phe 43 cavity; (3) enhancement of CD4-independent infection by NBD-556 requires the induction of conformational changes in gp120; and (4) increased affinity of NBD-556 analogs for gp120 improves antiviral potency during infection of CD4-expressing cells.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, JFB 824, Boston, MA 02115, USA.
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.forename: Arne
authors.initials: A
authors.lastname: Schön
authors.forename: Amy M
authors.initials: AM
authors.lastname: Princiotto
authors.forename: Judith M
authors.initials: JM
authors.lastname: Lalonde
authors.forename: Joel R
authors.initials: JR
authors.lastname: Courter
authors.forename: Takahiro
authors.initials: T
authors.lastname: Soeta
authors.forename: Danny
authors.initials: D
authors.lastname: Ng
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Evan T
authors.initials: ET
authors.lastname: Brower
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Xiang
authors.forename: Young Do
authors.initials: YD
authors.lastname: Kwon
authors.forename: Chih-Chin
authors.initials: CC
authors.lastname: Huang
authors.forename: Richard
authors.initials: R
authors.lastname: Wyatt
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000821:virology; D015704:CD4 Antigens / Q000737:chemistry / Q000502:physiology; D002151:Calorimetry; D017124:Conserved Sequence; D015699:HIV Envelope Protein gp120 / Q000737:chemistry*; D015497:HIV-1 / Q000737:chemistry / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D010649:Phenylalanine / Q000737:chemistry; D011487:Protein Conformation; D019718:Receptors, CXCR4 / Q000737:chemistry; D011994:Recombinant Proteins / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D015704:CD4 Antigens; C527276:CXCR4 protein, human; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D010649:Phenylalanine