Structure-aided design of antiviral drugs : Application of the method on HIV-1 protease and SIV reverse transcriptase

Abstract: Many efforts have been made to control the AIDS epidemic. Extensive studies have been done on the biology, biochemistry, and structural biology of HIV in the search for antiviral drugs. The viral-encoded enzymes reverse transcriptase and protease have been main targets for drug design.Our study on the HIV-1 protease involves the X-ray structure determination of ten complexes with C-terminally duplicated linear inhibitors and two complexes with C2-symmetric cyclic inhibitors. The structural study of the HIV-1 protease/linear inhibitors revealed several interesting properties of the protease, such as the flexibility of S2/S2' subsites, and the presence of coupled and symmetry restricted adaptation of the inhibitor binding subsites. We also found that the inhibitors adopted specific asymmetric conformation of their central parts, where only one of the gemdiol-hydroxyls is pointing toward the catalytic aspartates. The study of the C2-symmetric cyclic inhibitors showed that despite our efforts to promote a symmetric binding of the sulfamide compound, it seems prone to bind non-symmetrically. Our research has resulted in several highly competent inhibitor compounds.The work on sooty mangabey SIV reverse transcriptase (SIVsm RT) involves the expression,purification, characterization and studies of inhibition. A simple and efficient large-scalepreparation method was developed for SIVsm RT, in which processing of the p65/p65homodimer to the p65/p51 heterodimer was done with HIV-1 protease. The catalyticproperties of SIVsm RT were characterized. The sensitivity toward non-nucleoside inhibitorsNNI's) of SIVsm RT was distinct from HIV-1. By screening an inhibitor-library, two leadcompounds, MSK-046 and MSK-076 (IC50-values of ~10 µ), belonging to the PETT-serieswere identified.