1izh: Difference between revisions

Revision as of 20:37, 2 May 2008

Inhibitor of HIV protease with unusual binding mode potently inhibiting multi-resistant protease mutants

OverviewOverview

Protease inhibitors (PIs) are an important class of drugs for the treatment of HIV infection. However, in the course of treatment, resistant viral variants with reduced sensitivity to PIs often emerge and become a major obstacle to successful control of viral load. On the basis of a compound equipotently inhibiting HIV-1 and 2 proteases (PR), we have designed a pseudopeptide inhibitor, QF34, that efficiently inhibits a wide variety of PR variants. In order to analyze the potency of the inhibitor, we constructed PR species harboring the typical (signature) mutations that confer resistance to commercially available PIs. Kinetic analyses showed that these mutated PRs were inhibited up to 1,000-fold less efficiently by the clinically approved PIs. In contrast, all PR species were effectively inhibited by QF34. In a clinical study, we have monitored 30 HIV-positive patients in the Czech Republic undergoing highly active antiretroviral therapy, and have identified highly PI resistant variants. Kinetic analyses revealed that QF34 retained its subnanomolar potency against multi-drug resistant PR variants. X-ray crystallographic analysis and molecular modeling experiments explained the wide specificity of QF34: this inhibitor binds to the PR in an unusual manner, thus avoiding contact sites that are mutated upon resistance development, and the unusual binding mode and consequently the binding energy is therefore preserved in the complex with a resistant variant. These results suggest a promising route for the design of second-generation PIs that are active against a variety of resistant PR variants.

About this StructureAbout this Structure

1IZH is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.

ReferenceReference

Unusual binding mode of an HIV-1 protease inhibitor explains its potency against multi-drug-resistant virus strains., Weber J, Mesters JR, Lepsik M, Prejdova J, Svec M, Sponarova J, Mlcochova P, Skalicka K, Strisovsky K, Uhlikova T, Soucek M, Machala L, Stankova M, Vondrasek J, Klimkait T, Kraeusslich HG, Hilgenfeld R, Konvalinka J, J Mol Biol. 2002 Dec 6;324(4):739-54. PMID:12460574 Page seeded by OCA on Fri May 2 20:37:09 2008

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OCA

@@ Line 1: / Line 1: @@
 [[Image:1izh.gif|left|200px]]
- {{Structure
+<!--
-|PDB= 1izh |SIZE=350|CAPTION= <scene name='initialview01'>1izh</scene>, resolution 1.90&Aring;
+The line below this paragraph, containing "STRUCTURE_1izh", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=Q50:{(1S)-1-BENZYL-4-[3-CARBAMOYL-1-(1-CARBAMOYL-2-PHENYL-ETHYLCARBAMOYL)-(S)-PROPYLCARBAMOYL]-2-OXO-5-PHENYL-PENTYL}-CARBAMIC+ACID+TERT-BUTYL+ESTER'>Q50</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_1izh|  PDB=1izh  |  SCENE=  }}
-|RELATEDENTRY=[[1izi|1IZI]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1izh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1izh OCA], [http://www.ebi.ac.uk/pdbsum/1izh PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1izh RCSB]</span>
-}}
 '''Inhibitor of HIV protease with unusual binding mode potently inhibiting multi-resistant protease mutants'''
@@ Line 44: / Line 41: @@
 [[Category: Vondrasek, J.]]
 [[Category: Weber, J.]]
-[[Category: hiv-1 proteinase]]
+[[Category: Hiv-1 proteinase]]
-[[Category: potent inhibitor]]
+[[Category: Potent inhibitor]]
-[[Category: subsite binding]]
+[[Category: Subsite binding]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May  2 20:37:09 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 21:26:53 2008''