Structure‐Based Design, Synthesis and Evaluation of Chemical Probes Against the Multidrug‐Resistant HIV‐1 Protease

Objective: To design and test highly potent inhibitors against MDR (multidrug‐resistant) HIV‐1 protease. Background: Human immunodeficiency virus‐1 (HIV‐1) protease is a critical enzyme for viral replication. HIV‐1 protease is a homodimeric aspartyl protease. During rapid viral replication, due to lack of proof reading, mutations accumulate in the viral proteins causing conformational changes and resulting in clinical drug‐resistance. One such multi drug‐resistant clinical isolate 769 HIV‐1 protease ( Structure, Vol. 13, 1887‐1895, Dec 2005 ), with expanded active site cavity and wide open flaps, was chosen as a novel drug target. Methods and Results: In the current study, MDR HIV‐1 protease has been co‐crystallized with a library of peptides (resembling the CA/p2 cleavage site) for probing the expanded active site cavity. Crystal structures showed altered binding pockets in the expanded active site cavity of the protease. In‐silico P1 and P1` side chain optimization has been performed using these crystal structures. Six chemical probes, using combinatorial approach were designed to fit these altered binding pockets to enhance the potency and were synthesized and evaluated. Conclusions: Structure‐function studies of chemical probes aid in the mapping of the active site cavity of the MDR HIV‐1 protease and may be used in developing novel antiretroviral compounds.