Inhibitors for the zymogen-like liberation cleavage of HIV-1 protease

摘要

Because the gag-pol dimer, which is evidently responsible for the initial proteolytic activity, has a substrate specificity which differs slightly from the mature PR (or at least different catalytic constants), conventional PR inhibitors are not able to inhibit it optimally. The aim therefore is to find inhibitors which are able to inhibit specifically the initial cuts in the gag-pol polyprotein. The inhibitors described herein are based on two amino-acid sequences which are initially cut in the gag-pol polyprotein and differ in essential positions from the cleavage sites which are cleaved by the mature HIV-1 protease. The two amino-acid sequences suitable and preferred as cleavage sites of a proteolytically active gag-pol dimer are: P4 P3 P2 P1 P1' P2' P3' Arg-Gln-Ala-Asn * Phe-Leu-Arg Asp-Leu-Ala-Phe * Pro-Gln-Gly. The following inhibitors can be derived from these: IMAGE The underlined groups are merely examples and can be replaced by groups of comparable function. Use of the inhibitors as pharmaceuticals for inhibiting the replication of HIV-1 in infected people.