Thermodynamics of Binding of a Low-Molecular-Weight CD4 Mimetic to HIV-1 gp120

• Published in: Biochemistry (Easton) Vol. 45; no. 36; pp. 10973 - 10980
• Main Authors: Schön, Arne, Madani, Navid, Klein, Jeffrey C, Hubicki, Amy, Ng, Danny, Yang, Xinzhen, Smith, Amos B, Sodroski, Joseph, Freire, Ernesto
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12.09.2006
• Subjects: Animals; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Binding Sites; Binding, Competitive; Calorimetry - methods; CD4 Antigens - drug effects; CD4 Antigens - metabolism; Cell Line - drug effects; Cell Line - virology; Circular Dichroism; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - metabolism; HIV-1 - genetics; HIV-1 - pathogenicity; Human immunodeficiency virus 1; Humans; Molecular Mimicry; Oxalates - metabolism; Oxalates - pharmacology; Piperazines - metabolism; Piperazines - pharmacology; Piperidines - metabolism; Piperidines - pharmacology; Protein Conformation; Receptors, CCR5 - drug effects; Receptors, CCR5 - metabolism; Thermodynamics
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi061193r

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 HIV-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.