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Lipophilicity Influences Drug Binding to ?1-Acid Glycoprotein F1/S Variants But Not to the A Variant.

ABSTRACT: Human ?1-acid glycoprotein has genetic variants, the F1, S, and A variants, which can be separated isoelectrophoretically. These variants show differences in their affinity of binding to several drugs. In this study, we investigated the factors determining drug binding to these ?1-acid glycoprotein genetic variants using disopyramide, warfarin, and tamsulosin as marker compounds.Binding of the marker drugs to human ?1-acid glycoprotein was determined by ultra-filtration in the presence or absence of various other drugs. For screening of the ?1-acid glycoprotein variants to which the marker drugs became bound, the effects of various other drugs on their binding were studied. The binding data were analyzed using a competitive inhibition model and the relationship between the estimated dissociation constants and physicochemical properties, such as log P, was also analyzed.The binding of tamsulosin was significantly decreased by aprindine, carvedilol, erythromycin, thioridazine, and warfarin, but not by disopyramide. The dissociation constants of drugs bound to F1/S variants were significantly correlated with their lipophilicity, but those for the A variant were not.We were able to develop a simple screening method for determining individual ?1-acid glycoprotein variants to which drugs would bind. The binding of drugs to F1/S variants may be determined mainly by drug lipophilicity.

SUBMITTER: Hanada K

PROVIDER: S-EPMC5629133 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Lipophilicity Influences Drug Binding to α1-Acid Glycoprotein F1/S Variants But Not to the A Variant.

Hanada Kazuhiko K

Drugs in R&D 20170901 3

<h4>Objective</h4>Human α1-acid glycoprotein has genetic variants, the F1, S, and A variants, which can be separated isoelectrophoretically. These variants show differences in their affinity of binding to several drugs. In this study, we investigated the factors determining drug binding to these α1-acid glycoprotein genetic variants using disopyramide, warfarin, and tamsulosin as marker compounds.<h4>Methods</h4>Binding of the marker drugs to human α1-acid glycoprotein was determined by ultra-fi ...[more]

PMID: 28646384

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Project description:Chikungunya virus (CHIKV) is a reemerging arbovirus responsible for outbreaks of infection throughout Asia and Africa, causing an acute illness characterized by fever, rash, and polyarthralgia. Although CHIKV infects a broad range of host cells, little is known about how CHIKV binds and gains access to the target cell interior. In this study, we tested whether glycosaminoglycan (GAG) binding is required for efficient CHIKV replication using CHIKV vaccine strain 181/25 and clinical isolate SL15649. Preincubation of strain 181/25, but not SL15649, with soluble GAGs resulted in dose-dependent inhibition of infection. While parental Chinese hamster ovary (CHO) cells are permissive for both strains, neither strain efficiently bound to or infected mutant CHO cells devoid of GAG expression. Although GAGs appear to be required for efficient binding of both strains, they exhibit differential requirements for GAGs, as SL15649 readily infected cells that express excess chondroitin sulfate but that are devoid of heparan sulfate, whereas 181/25 did not. We generated a panel of 181/25 and SL15649 variants containing reciprocal amino acid substitutions at positions 82 and 318 in the E2 glycoprotein. Reciprocal exchange at residue 82 resulted in a phenotype switch; Gly(82) results in efficient infection of mutant CHO cells but a decrease in heparin binding, whereas Arg(82) results in reduced infectivity of mutant cells and an increase in heparin binding. These results suggest that E2 residue 82 is a primary determinant of GAG utilization, which likely mediates attenuation of vaccine strain 181/25.Chikungunya virus (CHIKV) infection causes a debilitating rheumatic disease that can persist for months to years, and yet there are no licensed vaccines or antiviral therapies. Like other alphaviruses, CHIKV displays broad tissue tropism, which is thought to be influenced by virus-receptor interactions. In this study, we determined that cell-surface glycosaminoglycans are utilized by both a vaccine strain and a clinical isolate of CHIKV to mediate virus binding. We also identified an amino acid polymorphism in the viral E2 attachment protein that influences utilization of glycosaminoglycans. These data enhance an understanding of the viral and host determinants of CHIKV cell entry, which may foster development of new antivirals that act by blocking this key step in viral infection.

Dataset Information

Lipophilicity Influences Drug Binding to ?1-Acid Glycoprotein F1/S Variants But Not to the A Variant.

Publications

Lipophilicity Influences Drug Binding to α1-Acid Glycoprotein F1/S Variants But Not to the A Variant.

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