The binding of HIV-1 protease inhibitors to human serum proteins

Arne Schön, Maria Del Mar Ingaramo, Ernesto Freire

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)221-230
Number of pages10
JournalBiophysical Chemistry
Issue number2-3
StatePublished - Sep 1 2003


  • AIDS
  • Calorimetry
  • HIV-1 protease
  • Human serum albumin
  • Protease inhibitor
  • α -acid glycoprotein

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Organic Chemistry


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