Extension of the polarity-dependent "switch phenomenon" of the gp120 binding domain as a target for antiviral chemotherapy.
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.
Graf von Stosch
A
A
Department of Pathochemistry, German Cancer Research Center, Heidelberg, Germany.
Kinzel
V
V
Reed
J
J
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism; D002942:Circular Dichroism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D011487:Protein Conformation; D012997:Solvents
D000998:Antiviral Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D010446:Peptide Fragments; D012997:Solvents