Selective plasma protein binding of antimalarial drugs to α1-acid glycoprotein

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Abstract

Human plasma protein binding of six antimalarial agents of quinoline and acridine types was investigated by using spectroscopic techniques, affinity chromatography, ultrafiltration and HPLC methods. Induced circular dichroism (ICD) spectra showed binding of amodiaquine (AMQ), primaquine (PRQ), tafenoquine (TFQ), and quinacrine (QR) to α1-acid glycoprotein (AAG), the serum level of which greatly increases in Plasmodium infections. Association constant (Ka) values of about 105-106 M-1 could be determined. Analysis of the ICD and UV spectra of the drug-AAG complexes suggested the inclusion of the ligands into the central hydrophobic cavity of the protein. Using the purified forms of the two main genetic variants of AAG, ICD data indicated the selective binding of AMQ and PRQ to the 'F1/S', while QR to the 'A' variant. Results of fluorescence experiments supported the AAG binding of these drugs and provided further insights into the binding details of TFQ and QR. Fluorescence and CD displacement experiments showed the high-affinity AAG binding of mefloquine (Ka ≈ 106 M-1). For this drug, inverse binding stereoselectivities were found with the 'F1/S' and 'A' genetic variants of AAG. HSA association constants estimated from affinity chromatography results lag behind (103-105 M-1) the similar values derived for AAG. In case of chloroquine, no significant binding interaction was found either with AAG or HSA. Pharmacological aspects of the results are discussed.

Original languageEnglish
Pages (from-to)3759-3772
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number7
DOIs
Publication statusPublished - Apr 1 2008

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Quinacrine
Antimalarials
Circular Dichroism
Protein Binding
Amodiaquine
Primaquine
Affinity chromatography
Blood Proteins
Glycoproteins
Affinity Chromatography
Acids
Fluorescence
Pharmaceutical Preparations
Mefloquine
Acridines
Stereoselectivity
Chloroquine
Ultrafiltration
Dichroism
Malaria

Keywords

  • Acute-phase reaction
  • Antimalarial drugs
  • Fluorescence probes
  • Genetic variants
  • Human serum α-acid glycoprotein
  • Human serum albumin
  • Induced circular dichroism
  • Malaria
  • Plasma protein binding
  • Stereoselective binding

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

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title = "Selective plasma protein binding of antimalarial drugs to α1-acid glycoprotein",
abstract = "Human plasma protein binding of six antimalarial agents of quinoline and acridine types was investigated by using spectroscopic techniques, affinity chromatography, ultrafiltration and HPLC methods. Induced circular dichroism (ICD) spectra showed binding of amodiaquine (AMQ), primaquine (PRQ), tafenoquine (TFQ), and quinacrine (QR) to α1-acid glycoprotein (AAG), the serum level of which greatly increases in Plasmodium infections. Association constant (Ka) values of about 105-106 M-1 could be determined. Analysis of the ICD and UV spectra of the drug-AAG complexes suggested the inclusion of the ligands into the central hydrophobic cavity of the protein. Using the purified forms of the two main genetic variants of AAG, ICD data indicated the selective binding of AMQ and PRQ to the 'F1/S', while QR to the 'A' variant. Results of fluorescence experiments supported the AAG binding of these drugs and provided further insights into the binding details of TFQ and QR. Fluorescence and CD displacement experiments showed the high-affinity AAG binding of mefloquine (Ka ≈ 106 M-1). For this drug, inverse binding stereoselectivities were found with the 'F1/S' and 'A' genetic variants of AAG. HSA association constants estimated from affinity chromatography results lag behind (103-105 M-1) the similar values derived for AAG. In case of chloroquine, no significant binding interaction was found either with AAG or HSA. Pharmacological aspects of the results are discussed.",
keywords = "Acute-phase reaction, Antimalarial drugs, Fluorescence probes, Genetic variants, Human serum α-acid glycoprotein, Human serum albumin, Induced circular dichroism, Malaria, Plasma protein binding, Stereoselective binding",
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T1 - Selective plasma protein binding of antimalarial drugs to α1-acid glycoprotein

AU - Zsila, F.

AU - Visy, J.

AU - Mády, G.

AU - Fitos, I.

PY - 2008/4/1

Y1 - 2008/4/1

N2 - Human plasma protein binding of six antimalarial agents of quinoline and acridine types was investigated by using spectroscopic techniques, affinity chromatography, ultrafiltration and HPLC methods. Induced circular dichroism (ICD) spectra showed binding of amodiaquine (AMQ), primaquine (PRQ), tafenoquine (TFQ), and quinacrine (QR) to α1-acid glycoprotein (AAG), the serum level of which greatly increases in Plasmodium infections. Association constant (Ka) values of about 105-106 M-1 could be determined. Analysis of the ICD and UV spectra of the drug-AAG complexes suggested the inclusion of the ligands into the central hydrophobic cavity of the protein. Using the purified forms of the two main genetic variants of AAG, ICD data indicated the selective binding of AMQ and PRQ to the 'F1/S', while QR to the 'A' variant. Results of fluorescence experiments supported the AAG binding of these drugs and provided further insights into the binding details of TFQ and QR. Fluorescence and CD displacement experiments showed the high-affinity AAG binding of mefloquine (Ka ≈ 106 M-1). For this drug, inverse binding stereoselectivities were found with the 'F1/S' and 'A' genetic variants of AAG. HSA association constants estimated from affinity chromatography results lag behind (103-105 M-1) the similar values derived for AAG. In case of chloroquine, no significant binding interaction was found either with AAG or HSA. Pharmacological aspects of the results are discussed.

AB - Human plasma protein binding of six antimalarial agents of quinoline and acridine types was investigated by using spectroscopic techniques, affinity chromatography, ultrafiltration and HPLC methods. Induced circular dichroism (ICD) spectra showed binding of amodiaquine (AMQ), primaquine (PRQ), tafenoquine (TFQ), and quinacrine (QR) to α1-acid glycoprotein (AAG), the serum level of which greatly increases in Plasmodium infections. Association constant (Ka) values of about 105-106 M-1 could be determined. Analysis of the ICD and UV spectra of the drug-AAG complexes suggested the inclusion of the ligands into the central hydrophobic cavity of the protein. Using the purified forms of the two main genetic variants of AAG, ICD data indicated the selective binding of AMQ and PRQ to the 'F1/S', while QR to the 'A' variant. Results of fluorescence experiments supported the AAG binding of these drugs and provided further insights into the binding details of TFQ and QR. Fluorescence and CD displacement experiments showed the high-affinity AAG binding of mefloquine (Ka ≈ 106 M-1). For this drug, inverse binding stereoselectivities were found with the 'F1/S' and 'A' genetic variants of AAG. HSA association constants estimated from affinity chromatography results lag behind (103-105 M-1) the similar values derived for AAG. In case of chloroquine, no significant binding interaction was found either with AAG or HSA. Pharmacological aspects of the results are discussed.

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KW - Plasma protein binding

KW - Stereoselective binding

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