Aziridine-based inhibitors of HIV-1 protease
J. Grün,1* M. Rieger,2 A. Welker ,3 J. Bodem,4 W. Kiefer,1 T. Schneider,1 T. Schirmeister,1 B. Engels,2 C. Sotriffer3
1Institute of Pharmacy and Biochemistry, University of Mainz, GERMANY, 2Institute of Physical and Theoretical Chemistry, University of Würzburg, GERMANY, 3 Institute of Pharmacy and Food Chemistry, University of Würzburg, GERMANY, 4Institute of Virology and Immunology, University of Würzburg, GERMANY *
The HIV-1 protease represents an aspartate protease essential for proper virion assembly and maturation. Many competitive inhibitors of this protease are available with FDA approval but there is a rapid rise of strains that encode mutant proteases resistant to these reversible protease inhibitors.1 We explored the ability of QM/MM models to accurately describe the inhibition reaction of the HIV-1 PR by epoxide- and aziridine-based inhibitors. In contrast to their epoxide counterparts, the mechanisms and binding modes of aziridine-based inhibitors have much more rarely been the subject of investigations, e.g. no X-ray measurements for complexes with HIV-1 PR or SIV PR exist. Computations predict their inhibition mechanism to be similar to that of epoxides, but differences result from the stronger basicity of the aziridine.2 Accordingly, aziridine-based inhibitors should be ideally suitable for aspartate proteases which act in more acidic environments.3
This was indeed shown by recent work. Employing docking approaches the HIV-PR structure is used to predict possible substitution patterns of such new inhibitors with improved binding affinities. We present synthetic approaches these new optimized aziridine-bases inhibitors
1.Metzner, K. J.; Rauch, P.; von Wyl, V.; Leemann, C.; Grube, C.; Kuster, H.; Boni, J.; Weber, R.; Gunthard, H. F. J Infect Dis 2010, 201, 1063.
2. Vicik, R.; Helten, H.; Schirmeister, T.; Engels, B. Chemmedchem 2006, 1, 1021.
3. Vicik, R.; Busemann, M.; Baumann, K.; Schirmeister, T. Curr Top Med Chem 2006, 6, 331.