Structure-based design and synthesis of an HIV-1 entry inhibitor exploiting X-ray and thermodynamic characterization

Judith M. LaLonde; Matthew Le-Khac; David M. Jones; Joel R. Courter; Jongwoo Park; Arne Schön; Amy M. Princiotto; Xueling Wu; John R. Mascola; Ernesto Freire; Joseph Sodroski; Navid Madani; Wayne A. Hendrickson; Amos B. Smith

doi:10.1021/ml300407y

Structure-based design and synthesis of an HIV-1 entry inhibitor exploiting X-ray and thermodynamic characterization

Judith M. LaLonde, Matthew Le-Khac, David M. Jones, Joel R. Courter, Jongwoo Park, Arne Schön, Amy M. Princiotto, Xueling Wu, John R. Mascola, Ernesto Freire, Joseph Sodroski, Navid Madani, Wayne A. Hendrickson, Amos B. Smith

Krieger School of Arts and Sciences

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

50 Scopus citations

Abstract

The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 entry inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a submicromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC₅₀ geometric mean titer of 1.7 and 14.0 μM, respectively), without promoting CD4-independent viral entry. The thermodynamic signatures indicate a binding preference for the (R,R)- over the (S,S)-enantiomer. The crystal structure of the small-molecule/gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4-gp120 interface is an effective tactic to enhance the neutralization potency of small-molecule HIV-1 entry inhibitors.

Original language	English (US)
Pages (from-to)	338-343
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	4
Issue number	3
DOIs	https://doi.org/10.1021/ml300407y
State	Published - Mar 14 2013

Keywords

CD4
HIV
X-ray crystallography
entry inhibitor
gp120
protein-protein interactions
structure-based drug design
thermodynamics
viral inhibition

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml300407y

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LaLonde, J. M., Le-Khac, M., Jones, D. M., Courter, J. R., Park, J., Schön, A., Princiotto, A. M., Wu, X., Mascola, J. R., Freire, E., Sodroski, J., Madani, N., Hendrickson, W. A., & Smith, A. B. (2013). Structure-based design and synthesis of an HIV-1 entry inhibitor exploiting X-ray and thermodynamic characterization. ACS Medicinal Chemistry Letters, 4(3), 338-343. https://doi.org/10.1021/ml300407y

LaLonde, JM, Le-Khac, M, Jones, DM, Courter, JR, Park, J, Schön, A, Princiotto, AM, Wu, X, Mascola, JR, Freire, E, Sodroski, J, Madani, N, Hendrickson, WA & Smith, AB 2013, 'Structure-based design and synthesis of an HIV-1 entry inhibitor exploiting X-ray and thermodynamic characterization', ACS Medicinal Chemistry Letters, vol. 4, no. 3, pp. 338-343. https://doi.org/10.1021/ml300407y

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abstract = "The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 entry inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a submicromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC50 geometric mean titer of 1.7 and 14.0 μM, respectively), without promoting CD4-independent viral entry. The thermodynamic signatures indicate a binding preference for the (R,R)- over the (S,S)-enantiomer. The crystal structure of the small-molecule/gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4-gp120 interface is an effective tactic to enhance the neutralization potency of small-molecule HIV-1 entry inhibitors.",

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AU - Schön, Arne

AU - Princiotto, Amy M.

AU - Wu, Xueling

AU - Mascola, John R.

AU - Freire, Ernesto

AU - Sodroski, Joseph

AU - Madani, Navid

AU - Hendrickson, Wayne A.

AU - Smith, Amos B.

PY - 2013/3/14

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N2 - The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 entry inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a submicromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC50 geometric mean titer of 1.7 and 14.0 μM, respectively), without promoting CD4-independent viral entry. The thermodynamic signatures indicate a binding preference for the (R,R)- over the (S,S)-enantiomer. The crystal structure of the small-molecule/gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4-gp120 interface is an effective tactic to enhance the neutralization potency of small-molecule HIV-1 entry inhibitors.

AB - The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 entry inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a submicromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC50 geometric mean titer of 1.7 and 14.0 μM, respectively), without promoting CD4-independent viral entry. The thermodynamic signatures indicate a binding preference for the (R,R)- over the (S,S)-enantiomer. The crystal structure of the small-molecule/gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4-gp120 interface is an effective tactic to enhance the neutralization potency of small-molecule HIV-1 entry inhibitors.

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Structure-based design and synthesis of an HIV-1 entry inhibitor exploiting X-ray and thermodynamic characterization

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Keywords

ASJC Scopus subject areas

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