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.