Determination of the Substrate Envelope for Multidrug‐Resistant HIV‐1 Protease

Objectives: Determine the substrate envelope for MDR HIV‐1 protease to guide antiviral drug design. Background: HIV‐1 protease, required for HIV replication, is a critical therapeutic target in the treatment of AIDS. Under drug selection pressure, HIV‐1 protease mutations give raise to multiple drug resistance. Crystallographic studies on substrate complexes of wide‐type HIV‐1 protease revealed a consensus substrate‐shape which is defined as the ‘substrate‐envelope’. Many drug resistant mutations occur where inhibitors protrude from this substrate‐envelope and may predict potential resistance. Methods and Results: We focus on MDR HIV‐1 protease to propose atomic details of drug resistance and the drug design of novel inhibitors. We co‐crystallized HIV‐1 protease with nine natural Gag and Gag‐Pol cleavage site peptides and solved the structures of these nine complexes. Based on these structural studies we determined the substrate envelope. Conclusions: All the nine natural substrate peptides show induced fit to MDR HIV‐1 protease, although the extent of induced fit varies. Furthermore, the positions of the substrate peptides are different from those in wide‐type HIV‐1 protease, which gives a unique substrate envelope of MDR HIV‐1 protease. This project is funded by NIH.