New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors
Department of Biochemistry and Molecular Pharmacology
Life Sciences | Medicine and Health Sciences
PURPOSE OF REVIEW: Drug resistance results when the balance between the binding of inhibitors and the turnover of substrates is perturbed in favor of the substrates. Resistance is quite widespread to the HIV-1 protease inhibitors permitting the protease to process its 10 different substrates. This processing of the substrates permits the virus HIV-1 to mature and become infectious. The design of HIV-1 protease inhibitors that closely fit within the substrate-binding region is proposed to be a strategy to avoid drug resistance.
RECENT FINDINGS: Cocrystal structures of HIV-1 protease with its substrates define an overlapping substrate-binding region or substrate envelope. Novel HIV-1 protease inhibitors that were designed to fit within this substrate envelope were found to retain high binding affinity and have a flat binding profile against a panel of drug-resistant HIV-1 proteases.
SUMMARY: The avoidance of drug resistance needs to be considered in the initial design of inhibitors to quickly evolving targets such as HIV-1 protease. Using a detailed knowledge of substrate binding appears to be a promising strategy for achieving this goal to obtain robust HIV-1 protease inhibitors.
DOI of Published Version
Curr Opin HIV AIDS. 2008 Nov;3(6):642-6. Link to article on publisher's site
Current opinion in HIV and AIDS
Nalam MN, Schiffer CA. (2009). New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors. Open Access Publications by UMMS Authors. https://doi.org/10.1097/COH.0b013e3283136cee. Retrieved from https://escholarship.umassmed.edu/oapubs/2021