Modulation of heme and myristate binding to human serum albumin by anti-HIV drugs: An optical and NMR spectroscopic study

Gabriella Fanali, Alessio Bocedi, Paolo Ascenzi, Mauro Fasano

Research output: Contribution to journalArticlepeer-review

Abstract

Human serum albumin (HSA) has an extraordinary ligand-binding capacity, and transports Fe(III)heme and medium- and long-chain fatty acids. In human immunodeficiency virus-infected patients the administered drugs bind to HSA and act as allosteric effectors. Here, the binding of Fe(III)heme to HSA in the presence of three representative anti-HIV drugs and myristate is investigated. Values of the dissociation equilibrium constant Kd for Fe(III)heme binding to HSA were determined at different myristate concentrations, in the absence and presence of anti-HIV drugs. Nuclear magnetic relaxation dispersion profiles of HSA-Fe(III)heme were measured, at different myristate concentrations, in the absence and presence of anti-HIV drugs. Structural bases for anti-HIV drug binding to HSA are provided by automatic docking simulation. Abacavir and nevirapine bind to HSA with Kd values of 1 × 10-6 and 2 × 10-6 m, respectively. Therefore, at concentrations used in therapy (in the 1-5 × 10-6 m range) abacavir and nevirapine bind to HSA and increase the affinity of heme for HSA. In the presence of abacavir or nevirapine, the affinity is not lowered by myristate. FA7 should therefore be intended as a secondary binding site for abacavir and nevirapine. Binding of atazanavir is limited by the large size of the drug, although preferential binding may be envisaged to a site positively coupled with FA1 and FA2, and negatively coupled to FA7. As a whole, these results provide a foundation for the comprehension of the complex network of links modulating HSA-binding properties.

Original languageEnglish
Pages (from-to)4491-4502
Number of pages12
JournalFEBS Journal
Volume274
Issue number17
DOIs
Publication statusPublished - Sep 2007

Keywords

  • Allosteric modulation
  • Anti-HIV drugs
  • Heterotropic interactions
  • Human serum albumin
  • NMR relaxation

ASJC Scopus subject areas

  • Biochemistry

Fingerprint

Dive into the research topics of 'Modulation of heme and myristate binding to human serum albumin by anti-HIV drugs: An optical and NMR spectroscopic study'. Together they form a unique fingerprint.

Cite this