Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120

Navid Madani; Arne Schön; Amy M. Princiotto; Judith M. LaLonde; Joel R. Courter; Takahiro Soeta; Danny Ng; Liping Wang; Evan T. Brower; Shi Hua Xiang; Young Do Kwon; Chih chin Huang; Richard Wyatt; Peter D. Kwong; Ernesto Freire; Amos B. Smith; Joseph Sodroski

doi:10.1016/j.str.2008.09.005

Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120

Navid Madani, Arne Schön, Amy M. Princiotto, Judith M. LaLonde, Joel R. Courter, Takahiro Soeta, Danny Ng, Liping Wang, Evan T. Brower, Shi Hua Xiang, Young Do Kwon, Chih chin Huang, Richard Wyatt, Peter D. Kwong, Ernesto Freire, Amos B. Smith, Joseph Sodroski

School of Medicine

Research output: Contribution to journal › Article › peer-review

139 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1689-1701
Number of pages	13
Journal	Structure
Volume	16
Issue number	11
DOIs	https://doi.org/10.1016/j.str.2008.09.005
State	Published - Nov 12 2008

Keywords

MICROBIO
MOLIMMUNO
PROTEINS

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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10.1016/j.str.2008.09.005

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Madani, N., Schön, A., Princiotto, A. M., LaLonde, J. M., Courter, J. R., Soeta, T., Ng, D., Wang, L., Brower, E. T., Xiang, S. H., Do Kwon, Y., Huang, C. C., Wyatt, R., Kwong, P. D., Freire, E., Smith, A. B., & Sodroski, J. (2008). Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120. Structure, 16(11), 1689-1701. https://doi.org/10.1016/j.str.2008.09.005

@article{4f54573d44ba477386e41298f818574b,

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.",

keywords = "MICROBIO, MOLIMMUNO, PROTEINS",

author = "Navid Madani and Arne Sch{\"o}n and Princiotto, {Amy M.} and LaLonde, {Judith M.} and Courter, {Joel R.} and Takahiro Soeta and Danny Ng and Liping Wang and Brower, {Evan T.} and Xiang, {Shi Hua} and {Do Kwon}, Young and Huang, {Chih chin} and Richard Wyatt and Kwong, {Peter D.} and Ernesto Freire and Smith, {Amos B.} and Joseph Sodroski",

note = "Funding Information: We thank Wayne Hendrickson and Irwin Chaiken for valuable discussion. We thank Yvette McLaughlin and Elizabeth Carpelan for manuscript preparation, and Jonathan Stuckey for preparation of figures. This study was supported by the National Institutes of Health (Grants GM56550, AI24755, and AI60354), the International AIDS Vaccine Initiative, and William F. McCarty-Cooper. ",

year = "2008",

month = nov,

day = "12",

doi = "10.1016/j.str.2008.09.005",

language = "English (US)",

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journal = "Structure",

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T1 - Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120

AU - Madani, Navid

AU - Schön, Arne

AU - Princiotto, Amy M.

AU - LaLonde, Judith M.

AU - Courter, Joel R.

AU - Soeta, Takahiro

AU - Ng, Danny

AU - Wang, Liping

AU - Brower, Evan T.

AU - Xiang, Shi Hua

AU - Do Kwon, Young

AU - Huang, Chih chin

AU - Wyatt, Richard

AU - Kwong, Peter D.

AU - Freire, Ernesto

AU - Smith, Amos B.

AU - Sodroski, Joseph

N1 - Funding Information: We thank Wayne Hendrickson and Irwin Chaiken for valuable discussion. We thank Yvette McLaughlin and Elizabeth Carpelan for manuscript preparation, and Jonathan Stuckey for preparation of figures. This study was supported by the National Institutes of Health (Grants GM56550, AI24755, and AI60354), the International AIDS Vaccine Initiative, and William F. McCarty-Cooper.

PY - 2008/11/12

Y1 - 2008/11/12

N2 - 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.

AB - 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.

KW - MICROBIO

KW - MOLIMMUNO

KW - PROTEINS

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ER -

Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120

Abstract

Keywords

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