INHIBITORS OF THE CONFORMATIONAL SWITCH INVOLVED IN CD4 BINDING BY THE ENV GLYCOPROTEIN GP120 FROM HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1)

A 15-residue fragment within the major continuous domain of gp120 from HIV1 that can bind independently to the CD4 receptor conserves the pr operty of behaving as a polarity-triggered conformational switch despi te displaying over 50% variability between strains. As this switch beh avior (the ability to flip abruptly from beta-sheet to alpha-helix as the medium polarity is lowered past a critical point) is closely linke d to CD4-binding ability, it presents a potential strain-independent t arget for intervention. A number of compounds have been tested for the ir ability to function as switch inhibitors. All those that displayed switch inhibitory activity also have been shown to act to prevent CD4 binding and/or viral infectivity. In addition, all compounds testing p ositive as switch inhibitors have certain chemical characteristics in common. The groundwork has thus been established for the design of str ain-independent blockers of CD4 binding based on the strategy of switc h inhibition.