Small-molecule CD4 mimics interact with a highly conserved pocket on HIV-1 gp120.
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.
Madani
Navid
N
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, JFB 824, Boston, MA 02115, USA.
Schön
Arne
A
Princiotto
Amy M
AM
Lalonde
Judith M
JM
Courter
Joel R
JR
Soeta
Takahiro
T
Ng
Danny
D
Wang
Liping
L
Brower
Evan T
ET
Xiang
Shi-Hua
SH
Kwon
Young Do
YD
Huang
Chih-Chin
CC
Wyatt
Richard
R
Kwong
Peter D
PD
Freire
Ernesto
E
Smith
Amos B
AB
Sodroski
Joseph
J
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
D015704:CD4 Antigens; C527276:CXCR4 protein, human; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D010649:Phenylalanine