BILE-PIGMENTS AS HIV-1 PROTEASE INHIBITORS AND THEIR EFFECTS ON HIV-1VIRAL MATURATION AND INFECTIVITY IN-VITRO

Using recently developed molecular-shape description algorithms, we se arched the Available Chemical Directory for known compounds similar in shape to the potent HIV-1 protease inhibitor Merck L-700,417; 15 comp ounds most similar in shape to the inhibitor were selected for testing in vitro. Four of these inhibited the protease at 100 mu M or less an d the most active of the four were the naturally occurring pigments bi liverdin and bilirubin. Biliverdin and bilirubin inhibited recombinant HIV-1 protease in vitro at pH 7.8 with K-i values of approx. 1 mu M, and also inhibited HIV-2 and simian immunodeficiency virus proteases. The related pyrrolic pigments stercobilin, urobilin, biliverdin dimeth yl ester and xanthobilirubic acid showed similar inhibitory activity a t low micromolar concentrations. Biliverdin, bilirubin and xanthobilir ubic acid did not inhibit viral polyprotein processing in cultured cel ls, but they reduced viral infectivity significantly. At 100 mu M, xan thobilirubic acid affected viral assembly, resulting in a 50% decrease in the generation of infectious particles. In contrast, at the same c oncentrations biliverdin and bilirubin exerted little or no effect on viral assembly but blocked infection of HeLaT4 cells by 50%. These res ults suggest that bile pigments might be a new class of potential lead compounds for developing protease inhibitors and they raise the quest ion of whether hyperbilirubinaemia can influence the course of HIV inf ection.