The alarming increase in drug resistant strains of HIV demands the discovery of new and potent inhibitorsfor effective disease management. An efficient way to synthesize and screen compounds is by using targetguided synthesis (TGS) where the target designs its own inhibitors. In this proposal a variant of TGS knownas 'in situ click chemistry' will be used to target a highly drug resistant HIV protease. An HIV templated 1,3-dipolarcycloaddition between an azide and an alkyne to form a triazole will be employed as the final bondforming reaction.
The specific aims of this proposal are to synthesize a library of twenty azides and ninealkynes and then combine all of them together in the presence of the protease. The rate of the normallyslow cycloaddition dramatically increases when the reaction components simultaneously bind to the target.Where the alkyne and the azide themselves may be modest inhibitors, the triazole is a much strongerbinder because it is accessing two binding pockets. Screening of the library is as simple as detectingtriazole formation which is easily accomplished by mass spectrometry. This work is a proof of principle and upon successful completion can be applied to any number of diseases for which and inhibitor is desired.
