1ztz
From Proteopedia
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==Overview== | ==Overview== | ||
| - | HIV protease (PR) represents a prime target for rational drug design, and | + | HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs are pseudopeptide compounds with limited bioavailability and stability, and their use is compromised by high costs, side effects, and development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral metallacarboranes, as candidates for a novel class of nonpeptidic PIs. Here, we report the potent, specific, and selective competitive inhibition of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a K(i) value of 2.2 nM and a submicromolar EC(50) in antiviral tests, showed no toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and was inactive against trypsin, papain, and amylase. The structure of the parent cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 A resolution by protein crystallography and represents the first carborane-protein complex structure determined. It shows the following mode of PR inhibition: two molecules of the parent compound bind to the hydrophobic pockets in the flap-proximal region of the S3 and S3' subsites of PR. We suggest, therefore, that these compounds block flap closure in addition to filling the corresponding binding pockets as conventional PIs. This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make boron clusters attractive pharmacophores for potent and specific enzyme inhibition. |
==About this Structure== | ==About this Structure== | ||
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[[Category: Konvalinka, J.]] | [[Category: Konvalinka, J.]] | ||
[[Category: Kozisek, M.]] | [[Category: Kozisek, M.]] | ||
| - | [[Category: Kraeusslich, H | + | [[Category: Kraeusslich, H G.]] |
[[Category: Kral, V.]] | [[Category: Kral, V.]] | ||
[[Category: Otwinowski, Z.]] | [[Category: Otwinowski, Z.]] | ||
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[[Category: rational drug design; hiv protease inhibitors; aspartic proteases; carboranes; metallacarboranes]] | [[Category: rational drug design; hiv protease inhibitors; aspartic proteases; carboranes; metallacarboranes]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:19:05 2008'' |
Revision as of 14:19, 21 February 2008
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Crystal structure of HIV protease- metallacarborane complex
Overview
HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs are pseudopeptide compounds with limited bioavailability and stability, and their use is compromised by high costs, side effects, and development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral metallacarboranes, as candidates for a novel class of nonpeptidic PIs. Here, we report the potent, specific, and selective competitive inhibition of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a K(i) value of 2.2 nM and a submicromolar EC(50) in antiviral tests, showed no toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and was inactive against trypsin, papain, and amylase. The structure of the parent cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 A resolution by protein crystallography and represents the first carborane-protein complex structure determined. It shows the following mode of PR inhibition: two molecules of the parent compound bind to the hydrophobic pockets in the flap-proximal region of the S3 and S3' subsites of PR. We suggest, therefore, that these compounds block flap closure in addition to filling the corresponding binding pockets as conventional PIs. This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make boron clusters attractive pharmacophores for potent and specific enzyme inhibition.
About this Structure
1ZTZ is a Single protein structure of sequence from Human immunodeficiency virus 1 with as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
Reference
From nonpeptide toward noncarbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease., Cigler P, Kozisek M, Rezacova P, Brynda J, Otwinowski Z, Pokorna J, Plesek J, Gruner B, Doleckova-Maresova L, Masa M, Sedlacek J, Bodem J, Krausslich HG, Kral V, Konvalinka J, Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15394-9. Epub 2005 Oct 14. PMID:16227435
Page seeded by OCA on Thu Feb 21 16:19:05 2008
Categories: HIV-1 retropepsin | Human immunodeficiency virus 1 | Single protein | Bodem, J. | Brynda, J. | Cigler, P. | Konvalinka, J. | Kozisek, M. | Kraeusslich, H G. | Kral, V. | Otwinowski, Z. | Rezacova, P. | Sedlacek, J. | CB5 | Rational drug design; hiv protease inhibitors; aspartic proteases; carboranes; metallacarboranes
