1sbg
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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) with IM1 as ligand. 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
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