title: The binding of HIV-1 protease inhibitors to human serum proteins.
abstract: 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 alpha(1)-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 (K(a) approximately 0.5-10 x 10(5) M(-1)) and a relatively low affinity for HSA (K(a) approximately 5-15 x 10(3) 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.
mesh_terms: D001682:Biological Availability; D001798:Blood Proteins / Q000737:chemistry*; D002151:Calorimetry; D016333:HIV Protease / Q000737:chemistry*; D006801:Humans; D009961:Orosomucoid / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D001798:Blood Proteins; D009961:Orosomucoid; D011480:Protease Inhibitors; D012709:Serum Albumin; D016333:HIV Protease