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

Zhigang Liu; Ravikiran S. Yedidi; Yong Wang; Tamaria G. Dewdney; Samuel J. Reiter; Joseph S. Brunzelle; Iulia A. Kovari; Ladislau C. Kovari

doi:10.1016/j.bbrc.2012.12.127

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

Zhigang Liu, Ravikiran S. Yedidi, Yong Wang, Tamaria G. Dewdney, Samuel J. Reiter, Joseph S. Brunzelle, Iulia A. Kovari, Ladislau C. Kovari^*

^*Corresponding author for this work

NSRC - Northwestern Synchrotron Research Center - LS CAT

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	232-238
Number of pages	7
Journal	Biochemical and Biophysical Research Communications
Volume	431
Issue number	2
DOIs	https://doi.org/10.1016/j.bbrc.2012.12.127
State	Published - Feb 8 2013

Keywords

HIV-1 protease
IC50
Multi-drug resistance
Ritonavir
X-ray crystallography

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

Access to Document

10.1016/j.bbrc.2012.12.127

Fingerprint Dive into the research topics of 'Insights into the mechanism of drug resistance: X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex'. Together they form a unique fingerprint.

Cite this

Liu, Zhigang ; Yedidi, Ravikiran S. ; Wang, Yong ; Dewdney, Tamaria G. ; Reiter, Samuel J. ; Brunzelle, Joseph S. ; Kovari, Iulia A. ; Kovari, Ladislau C. / Insights into the mechanism of drug resistance : X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex. In: Biochemical and Biophysical Research Communications. 2013 ; Vol. 431, No. 2. pp. 232-238.

@article{fe72dca7e7d54121aeb76f8b8d5d5f8d,

title = "Insights into the mechanism of drug resistance: X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex",

abstract = "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.",

keywords = "HIV-1 protease, IC50, Multi-drug resistance, Ritonavir, X-ray crystallography",

author = "Zhigang Liu and Yedidi, {Ravikiran S.} and Yong Wang and Dewdney, {Tamaria G.} and Reiter, {Samuel J.} and Brunzelle, {Joseph S.} and Kovari, {Iulia A.} and Kovari, {Ladislau C.}",

note = "Funding Information: This research was supported by the National Institutes of Health Grant AI65294 and a Grant from the American Foundation for AIDS Research ( 106457-34-RGGN ). ",

year = "2013",

month = feb,

day = "8",

doi = "10.1016/j.bbrc.2012.12.127",

language = "English (US)",

volume = "431",

pages = "232--238",

journal = "Biochemical and Biophysical Research Communications",

issn = "0006-291X",

publisher = "Academic Press Inc.",

number = "2",

}

Insights into the mechanism of drug resistance : X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex. / Liu, Zhigang; Yedidi, Ravikiran S.; Wang, Yong; Dewdney, Tamaria G.; Reiter, Samuel J.; Brunzelle, Joseph S.; Kovari, Iulia A.; Kovari, Ladislau C.

In: Biochemical and Biophysical Research Communications, Vol. 431, No. 2, 08.02.2013, p. 232-238.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Insights into the mechanism of drug resistance

T2 - X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex

AU - Liu, Zhigang

AU - Yedidi, Ravikiran S.

AU - Wang, Yong

AU - Dewdney, Tamaria G.

AU - Reiter, Samuel J.

AU - Brunzelle, Joseph S.

AU - Kovari, Iulia A.

AU - Kovari, Ladislau C.

N1 - Funding Information: This research was supported by the National Institutes of Health Grant AI65294 and a Grant from the American Foundation for AIDS Research ( 106457-34-RGGN ).

PY - 2013/2/8

Y1 - 2013/2/8

N2 - 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.

AB - 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.

KW - HIV-1 protease

KW - IC50

KW - Multi-drug resistance

KW - Ritonavir

KW - X-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=84873435058&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873435058&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2012.12.127

DO - 10.1016/j.bbrc.2012.12.127

M3 - Article

C2 - 23313846

AN - SCOPUS:84873435058

VL - 431

SP - 232

EP - 238

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 2

ER -