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1sbg

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{{STRUCTURE_1sbg| PDB=1sbg | SCENE= }}
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'''AN ORALLY-BIOAVAILABLE HIV-1 PROTEASE INHIBITOR CONTAINING AN IMIDAZOLE-DERIVED PEPTIDE BOND REPLACEMENT. CRYSTALLOGRAPHIC AND PHARMACOKINETIC ANALYSIS'''
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===AN ORALLY-BIOAVAILABLE HIV-1 PROTEASE INHIBITOR CONTAINING AN IMIDAZOLE-DERIVED PEPTIDE BOND REPLACEMENT. CRYSTALLOGRAPHIC AND PHARMACOKINETIC ANALYSIS===
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==Overview==
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(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.
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(as it appears on PubMed at http://www.pubmed.gov), where 7918383 is the PubMed ID number.
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{{ABSTRACT_PUBMED_7918383}}
==About this Structure==
==About this Structure==
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[[Category: Abdel-Meguid, S.]]
[[Category: Abdel-Meguid, S.]]
[[Category: Zhao, B.]]
[[Category: Zhao, B.]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 15:46:28 2008''

Revision as of 12:46, 29 July 2008

Image:1sbg.png

Template:STRUCTURE 1sbg

AN ORALLY-BIOAVAILABLE HIV-1 PROTEASE INHIBITOR CONTAINING AN IMIDAZOLE-DERIVED PEPTIDE BOND REPLACEMENT. CRYSTALLOGRAPHIC AND PHARMACOKINETIC ANALYSIS

Template:ABSTRACT PUBMED 7918383

About 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.

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

Page seeded by OCA on Tue Jul 29 15:46:28 2008

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OCA, Eric Martz

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