1sbg: Difference between revisions
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'''AN ORALLY-BIOAVAILABLE HIV-1 PROTEASE INHIBITOR CONTAINING AN IMIDAZOLE-DERIVED PEPTIDE BOND REPLACEMENT. CRYSTALLOGRAPHIC AND PHARMACOKINETIC ANALYSIS''' | '''AN ORALLY-BIOAVAILABLE HIV-1 PROTEASE INHIBITOR CONTAINING AN IMIDAZOLE-DERIVED PEPTIDE BOND REPLACEMENT. CRYSTALLOGRAPHIC AND PHARMACOKINETIC ANALYSIS''' | ||
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==Reference== | ==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:[http://www.ncbi.nlm.nih.gov/pubmed/7918383 7918383] | 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:[http://www.ncbi.nlm.nih.gov/pubmed/7918383 7918383] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Abdel-Meguid, S.]] | [[Category: Abdel-Meguid, S.]] | ||
[[Category: Zhao, B.]] | [[Category: Zhao, B.]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 08:30:42 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 08:30, 3 May 2008
AN ORALLY-BIOAVAILABLE HIV-1 PROTEASE INHIBITOR CONTAINING AN IMIDAZOLE-DERIVED PEPTIDE BOND REPLACEMENT. CRYSTALLOGRAPHIC AND PHARMACOKINETIC ANALYSIS
OverviewOverview
(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 StructureAbout this Structure
1SBG is a Single protein structure of sequence from Human immunodeficiency virus type 1 (isolate bh10). Full crystallographic information is available from OCA.
ReferenceReference
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 Page seeded by OCA on Sat May 3 08:30:42 2008