A systematic study of P1–P3 spanning sidechains for the inhibition of HIV-1 protease

Using information obtained from the co-crystal structure of an initial peptidomimetic lead complexed with HIV-1 protease, a series of inhibitors was constructed with substituents designed to span from the P1 to the P3 pockets of the enzyme. In accord with prediction, systematic extension of the P1 substituent with large, lipophilic groups leads to enhancements in binding potencies for this class of inhibitors. Surprisingly, inhibitors with large substituents at both P1 and P3 are also well-tolerated by the enzyme, providing compounds with subnanomolar binding affinities for HIV-1 protease.