TY - JOUR
T1 - The binding of HIV-1 protease inhibitors to human serum proteins
AU - Schön, Arne
AU - Del Mar Ingaramo, Maria
AU - Freire, Ernesto
N1 - Funding Information:
Supported by the National Institutes of Health grant GM 57144.
PY - 2003/9/1
Y1 - 2003/9/1
N2 - The non-specific binding of a drug to plasma proteins is an important determinant of its biological efficacy since it modulates the availability of the drug to its intended target. In the case of HIV-1 protease inhibitors, binding to human serum albumin (HSA) and α1-acid glycoprotein (AAG) appears to be an important modulator of drug bioavailability. From a thermodynamic point of view, the issue of drug availability to the desired target can be formulated as a multiple equilibrium problem in which a ligand is able to bind to different proteins or other macromolecules with different binding affinities. Previously, we have measured the binding thermodynamics of HIV-1 protease inhibitors to their target. In this article, the binding energetics of four inhibitors currently in clinical use (saquinavir, indinavir, ritonavir and nelfinavir) and a second-generation inhibitor (KNI-764) to human HSA and AAG has been studied by isothermal titration calorimetry. All inhibitors exhibited a significant affinity for AAG (Ka∼ 0.5-10×105 M-1) and a relatively low affinity for HSA (Ka∼5-15×103 M-1). It is shown that under conditions that simulate in vivo concentrations of serum proteins, the inhibitor concentrations required to achieve 95% protease inhibition can be up to 10 times higher than those required in the absence of serum proteins. The effect is compounded in patients infected with drug resistant HIV-1 strains that exhibit a lower affinity for protease inhibitors. In these cases the required inhibitor concentrations can be up to 2000 times higher and beyond the solubility limits of the inhibitors.
AB - The non-specific binding of a drug to plasma proteins is an important determinant of its biological efficacy since it modulates the availability of the drug to its intended target. In the case of HIV-1 protease inhibitors, binding to human serum albumin (HSA) and α1-acid glycoprotein (AAG) appears to be an important modulator of drug bioavailability. From a thermodynamic point of view, the issue of drug availability to the desired target can be formulated as a multiple equilibrium problem in which a ligand is able to bind to different proteins or other macromolecules with different binding affinities. Previously, we have measured the binding thermodynamics of HIV-1 protease inhibitors to their target. In this article, the binding energetics of four inhibitors currently in clinical use (saquinavir, indinavir, ritonavir and nelfinavir) and a second-generation inhibitor (KNI-764) to human HSA and AAG has been studied by isothermal titration calorimetry. All inhibitors exhibited a significant affinity for AAG (Ka∼ 0.5-10×105 M-1) and a relatively low affinity for HSA (Ka∼5-15×103 M-1). It is shown that under conditions that simulate in vivo concentrations of serum proteins, the inhibitor concentrations required to achieve 95% protease inhibition can be up to 10 times higher than those required in the absence of serum proteins. The effect is compounded in patients infected with drug resistant HIV-1 strains that exhibit a lower affinity for protease inhibitors. In these cases the required inhibitor concentrations can be up to 2000 times higher and beyond the solubility limits of the inhibitors.
KW - AIDS
KW - Calorimetry
KW - HIV-1 protease
KW - Human serum albumin
KW - Protease inhibitor
KW - α -acid glycoprotein
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U2 - 10.1016/S0301-4622(03)00071-1
DO - 10.1016/S0301-4622(03)00071-1
M3 - Article
C2 - 14499894
AN - SCOPUS:0141672041
SN - 0301-4622
VL - 105
SP - 221
EP - 230
JO - Biophysical Chemistry
JF - Biophysical Chemistry
IS - 2-3
ER -