Thermodynamics of binding of a low-molecular-weight CD4 mimetic to HIV-1 gp120.
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 x 10(5) M(-1) (K(d) = 3.7 muM) 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.
Schön
Arne
A
Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
Madani
Navid
N
Klein
Jeffrey C
JC
Hubicki
Amy
A
Ng
Danny
D
Yang
Xinzhen
X
Smith
Amos B
AB
Sodroski
Joseph
J
Freire
Ernesto
E
D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D015704:CD4 Antigens / Q000187:drug effects / Q000378:metabolism*; D002151:Calorimetry / Q000379:methods; D002460:Cell Line / Q000187:drug effects / Q000821:virology; D002942:Circular Dichroism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D018716:Molecular Mimicry; D010070:Oxalates / Q000378:metabolism* / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000187:drug effects / Q000378:metabolism; D013816:Thermodynamics
D019380:Anti-HIV Agents; C477855:BMS-378806; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; C514247:N-(4-bromophenyl)-N'-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide; C514246:N-(4-chlorophenyl)-N'-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide; D010070:Oxalates; D010879:Piperazines; D010880:Piperidines; D019713:Receptors, CCR5