1sbg
From Proteopedia
(New page: 200px<br /> <applet load="1sbg" size="450" color="white" frame="true" align="right" spinBox="true" caption="1sbg, resolution 2.3Å" /> '''AN ORALLY-BIOAVAILAB...) |
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caption="1sbg, resolution 2.3Å" /> | caption="1sbg, resolution 2.3Å" /> | ||
'''AN ORALLY-BIOAVAILABLE HIV-1 PROTEASE INHIBITOR CONTAINING AN IMIDAZOLE-DERIVED PEPTIDE BOND REPLACEMENT. CRYSTALLOGRAPHIC AND PHARMACOKINETIC ANALYSIS'''<br /> | '''AN ORALLY-BIOAVAILABLE HIV-1 PROTEASE INHIBITOR CONTAINING AN IMIDAZOLE-DERIVED PEPTIDE BOND REPLACEMENT. CRYSTALLOGRAPHIC AND PHARMACOKINETIC ANALYSIS'''<br /> | ||
==Overview== | ==Overview== | ||
| - | (2R,4S,5S,1'S)-2-Phenylmethyl-4-hydroxy-5-(tert-butoxycarbonyl) | + | (2R,4S,5S,1'S)-2-Phenylmethyl-4-hydroxy-5-(tert-butoxycarbonyl) amino-6-phenylhexanoyl-N-(1'-imidazo-2-yl)-2'-methylpropanamide (compound 2) is a tripeptide analogue inhibitor of HIV-1 protease in which a C-terminal imidazole substituent constitutes an isoelectronic, structural mimic of a carboxamide group. Compound 2 is a potent inhibitor of the protease (K(i) = 18 nM) and inhibits HIV-1 acute infectivity of CD4+ T-lymphocytes (IC50 = 570 nM). Crystallographic analysis of an HIV-1 protease-compound 2 complex demonstrates that the nitrogen atoms of the imidazole ring assume the same hydrogen-bonding interactions with the protease as amide linkages in other peptide analogue inhibitors. The sole substitution of the C-terminal carboxamide of a hydroxyethylene-containing tripeptide analogue with an imidazole group imparts greatly improved pharmacokinetic and oral bioavailability properties on the compound compared to its carboxamide-containing homologue (compound 1). While the oral bioavailability of compound 1 in rats was negligible, compound 2 displayed oral bioavailabilities of 30% and 14%, respectively, in rats and monkeys. |
==About this Structure== | ==About this Structure== | ||
| - | 1SBG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_type_1_(isolate_bh10) Human immunodeficiency virus type 1 (isolate bh10)] with IM1 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1SBG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_type_1_(isolate_bh10) Human immunodeficiency virus type 1 (isolate bh10)] with <scene name='pdbligand=IM1:'>IM1</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SBG OCA]. |
==Reference== | ==Reference== | ||
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[[Category: hydrolase(acid protease)]] | [[Category: hydrolase(acid protease)]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:59:45 2008'' |
Revision as of 12:59, 21 February 2008
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AN ORALLY-BIOAVAILABLE HIV-1 PROTEASE INHIBITOR CONTAINING AN IMIDAZOLE-DERIVED PEPTIDE BOND REPLACEMENT. CRYSTALLOGRAPHIC AND PHARMACOKINETIC ANALYSIS
Overview
(2R,4S,5S,1'S)-2-Phenylmethyl-4-hydroxy-5-(tert-butoxycarbonyl) amino-6-phenylhexanoyl-N-(1'-imidazo-2-yl)-2'-methylpropanamide (compound 2) is a tripeptide analogue inhibitor of HIV-1 protease in which a C-terminal imidazole substituent constitutes an isoelectronic, structural mimic of a carboxamide group. Compound 2 is a potent inhibitor of the protease (K(i) = 18 nM) and inhibits HIV-1 acute infectivity of CD4+ T-lymphocytes (IC50 = 570 nM). Crystallographic analysis of an HIV-1 protease-compound 2 complex demonstrates that the nitrogen atoms of the imidazole ring assume the same hydrogen-bonding interactions with the protease as amide linkages in other peptide analogue inhibitors. The sole substitution of the C-terminal carboxamide of a hydroxyethylene-containing tripeptide analogue with an imidazole group imparts greatly improved pharmacokinetic and oral bioavailability properties on the compound compared to its carboxamide-containing homologue (compound 1). While the oral bioavailability of compound 1 in rats was negligible, compound 2 displayed oral bioavailabilities of 30% and 14%, respectively, in rats and monkeys.
About this Structure
1SBG is a Single protein structure of sequence from Human immunodeficiency virus type 1 (isolate bh10) with as ligand. Full crystallographic information is available from OCA.
Reference
An orally bioavailable HIV-1 protease inhibitor containing an imidazole-derived peptide bond replacement: crystallographic and pharmacokinetic analysis., Abdel-Meguid SS, Metcalf BW, Carr TJ, Demarsh P, DesJarlais RL, Fisher S, Green DW, Ivanoff L, Lambert DM, Murthy KH, et al., Biochemistry. 1994 Oct 4;33(39):11671-7. PMID:7918383
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