New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



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

Journal/Book/Conference Title

Current opinion in HIV and AIDS

Related Resources

Link to Article in PubMed

PubMed ID