Extension of the polarity-dependent switch phenomenon of the gp120 binding domain as a target for antiviral chemotherapy.

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

Extension of the polarity-dependent switch phenomenon of the gp120 binding domain as a target for antiviral chemotherapy.

Biochemistry. 1996 Jan 16;35(2):411-7. Unique Identifier : AIDSLINE MED/96140213
Graf von Stosch A; Kinzel V; Reed J; Department of Pathochemistry, German Cancer Research Center,; Heidelberg, Germany.

Abstract: A 15-residue fragment within the major continuous domain of gp120 from HIV-1 that can bind independently to the CD4 receptor has been shown to have the property of behaving as a solvent polarity-dependent conformational switch. The switch behavior (cooperative transition from beta-sheet to helical conformation as a function of solvent polarity), which is conserved among strains with the widest sequence variability possible, appears to be a prerequisite for the CD4-binding ability. A number of switch inhibitors have been identified that destroy the conformational switch in the 15-residue fragment and concurrently its ability to bind to CD4-expressing cells. It can now be shown that the switch behavior and its inhibition by substances with certain shared structural characteristics are not restricted to the 15-residue subfragment, but are reflected by the behavior of the entire 44-residue binding domain. Further, substances active as switch inhibitors have an immediate effect on the conformation of the 44-residue fragment in aqueous buffer whereas inactive substances do not. The predictive value of this as a screening method is demonstrated in testing a number of new potential switch inhibitory compounds.

Keywords: Amino Acid Sequence Antigens, CD4/METABOLISM Antiviral Agents/*PHARMACOLOGY Binding Sites Circular Dichroism Drug Screening/METHODS Human HIV Envelope Protein gp120/CHEMISTRY/*DRUG EFFECTS/GENETICS HIV-1/CHEMISTRY/*DRUG EFFECTS/GENETICS In Vitro Molecular Sequence Data Molecular Structure Nuclear Magnetic Resonance Peptide Fragments/CHEMISTRY/DRUG EFFECTS/GENETICS Protein Conformation Solvents JOURNAL ARTICLE
960530
M9651070

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