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 confo rmational switch. The switch behavior (cooperative transition from bet a-sheet to helical conformation as a function of solvent polarity), wh ich is conserved among strains with the widest sequence variability po ssible, appears to be a prerequisite for the CD4-binding ability. A nu mber of switch inhibitors have been identified that destroy the confor mational switch in the 15-residue fragment and concurrently its abilit y to bind to CD4-expressing cells. It can now be shown that the switch behavior and its inhibition by substances with certain shared structu ral characteristics are not restricted to the 15-residue subfragment, but are reflected by the behavior of the entire 44-residue binding dom ain. Further, substances active as switch inhibitors have an immediate effect on the conformation of the 44-residue fragment in aqueous buff er whereas inactive substances do not. The predictive value of this as a screening method is demonstrated in testing a number of new potenti al switch inhibitory compounds.