Insights into the mechanism of drug resistance. X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex

Journal Article · Tue Jan 08 00:00:00 EST 2013 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2012.12.127· OSTI ID:1064473

Liu, Zhigang ^[1]; Yedidi, Ravikiran S. ^[2]; Wang, Yong ^[3]; Dewdney, Tamaria G. ^[3]; Reiter, Samuel J. ^[3]; Brunzelle, Joseph S. ^[4]; Kovari, Iulia A. ^[3]; Kovari, Ladislau C. ^[3]

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1. Wayne State Univ., Detroit, MI (United States); Harbor Hospital Baltimore, MD (United States)
2. Wayne State Univ., Detroit, MI (United States); National Inst. of Health (NIH), Bethesda, MD (United States)
3. Wayne State Univ., Detroit, MI (United States)
4. Northwestern Univ., Chicago, IL (United States)

Ritonavir (RTV) is a first generation HIV-1 protease inhibitor with rapidly emerging drug resistance. Mutations at residues 46, 54, 82 and 84 render the HIV-1 protease drug resistant against RTV. We report the crystal structure of multi-drug resistant (MDR) 769 HIV-1 protease (carrying resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84 and 90) complexed with RTV and the in vitro enzymatic IC50 of RTV against MDR HIV-1 protease. The structural and functional studies demonstrate significant drug resistance of MDR HIV-1 protease against RTV, arising from reduced hydrogen bonds and Van der Waals interactions between RTV and MDR HIV-1 protease.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: National Institutes of Health, New York, NY (United States)
• OSTI ID: 1064473
• Journal Information: Biochemical and Biophysical Research Communications, Vol. 431, Issue (2) ; 02, 2013; ISSN 0006-291X
• Publisher: Elsevier
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

HIV-1 protease
multi-drug resistance
x-ray crystallography
IC50
ritonavir