Thermodynamics of binding of a low-molecular-weight CD4 mimetic to HIV-1 gp120

Arne Schön, Navid Madani, Jeffrey C. Klein, Amy Hubicki, Danny Ng, Xinzhen Yang, Amos B. Smith, Joseph Sodroski, Ernesto Freire

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Abstract

NBD-556 and the chemically and structurally similar NBD-557 are two low-molecular weight compounds that reportedly block the interaction between the HIV-1 envelope glycoprotein gp120 and its receptor, CD4. NBD-556 binds to gp120 with a binding affinity of 2.7 × 105 M-1 (K d = 3.7 μM) in a process characterized by a large favorable change in enthalpy partially compensated by a large unfavorable entropy change, a thermodynamic signature similar to that observed for binding of sCD4 to gp120. NBD-556 binding is associated with a large structuring of the gp120 molecule, as also demonstrated by CD spectroscopy. NBD-556, like CD4, activates the binding of gp120 to the HIV-1 coreceptor, CCR5, and to the 17b monoclonal antibody, which recognizes the coreceptor binding site of gp120. NBD-556 stimulates HIV-1 infection of CD4-negative, CCR5-expressing cells. The thermodynamic signature of the binding of NBD-556 to gp120 is very different from that of another viral entry inhibitor, BMS-378806. Whereas NBD-556 binds gp120 with a large favorable enthalpy and compensating unfavorable entropy changes, BMS-378806 does so with a small binding enthalpy change in a mostly entropy-driven process. NBD-556 is a competitive inhibitor of sCD4 and elicits a similar structuring of the coreceptor binding site, whereas BMS-378806 does not compete with sCD4 and does not induce coreceptor binding. These studies demonstrate that low-molecular-weight compounds can induce conformational changes in the HTV-1 gp120 glycoprotein similar to those observed upon CD4 binding, revealing distinct strategies for inhibiting the function of the HIV-1 gp120 envelope glycoprotein. Furthermore, competitive and noncompetitive compounds have characteristic thermodynamic signatures that can be used to guide the design of more potent and effective viral entry inhibitors.

Original languageEnglish (US)
Pages (from-to)10973-10980
Number of pages8
JournalBiochemistry
Volume45
Issue number36
DOIs
StatePublished - Sep 12 2006

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Schön, A., Madani, N., Klein, J. C., Hubicki, A., Ng, D., Yang, X., Smith, A. B., Sodroski, J., & Freire, E. (2006). Thermodynamics of binding of a low-molecular-weight CD4 mimetic to HIV-1 gp120. Biochemistry, 45(36), 10973-10980. https://doi.org/10.1021/bi061193r