Document 0895
 DOCN  M9440895
 TI    Evaluation of a vitamin-cloaking strategy for oligopeptide therapeutics:
       biotinylated HIV-1 protease inhibitors.
 DT    9404
 AU    Islam I; Ng KY; Chong KT; McQuade TJ; Hui JO; Wilkinson KF; Rush BD;
       Ruwart MJ; Borchardt RT; Fisher JF; Department of Medicinal Chemistry,
       Upjohn Laboratories, Upjohn; Company, Kalamazoo, Michigan 49001.
 SO    J Med Chem. 1994 Jan 21;37(2):293-304. Unique Identifier : AIDSLINE
       MED/94125429
 AB    The outstanding limitations to the oligopeptide as a therapeutic agent
       are poor oral availability and rapid biliary clearance. To address these
       concerns a series of eight peptidic HIV-1 protease inhibitors containing
       the structural segment of the vitamin biotin have been prepared. These
       have been evaluated with regard to the hypothesis that this vitamin
       would cloak the peptidic character of these oligopeptides, and thus
       impart to these inhibitors the potential for absorption and distribution
       via biotin transporters and receptors. By iterative optimization about a
       -Cha psi[CH-(OH)CH(OH)]Val- core inhibitory insert, three particularly
       potent inhibitors (K(i) < or = 10 nM) of the HIV-1 protease were
       obtained. Although excellent cell culture antiviral activity is observed
       for other peptidic protease inhibitors of comparable affinity, none in
       this series exhibited satisfactory antiviral activity. This failure is
       attributed to the incompatibility of the hydrophilic and
       hydrogen-bonding biotin segment, with the facile membrane permeability
       and intracellular access presumably required for antiviral activity. The
       ability of the biotin to cloak the peptide, and thus render the overall
       appearance of the conjugate as that of a vitamin, was evaluated. Four of
       this series were evaluated for recognition by the Caco-2 cell intestinal
       biotin transporter. None inhibited competitively biotin uptake,
       indicating a lack of recognition. A vitamin may bind to a specific
       protein carrier, and thus attain an improved serum profile (by
       resistance to biliary clearance) and advantageous delivery to cells.
       Therefore, the serum concentrations of three were evaluated following an
       iv bolus in a rat model for serum clearance. One of the three protease
       inhibitors (L-idonamide,
       6-cyclohexyl-2,5,6-trideoxy-2-(1-methylethyl)-5-[[3-methyl-1-oxo--
       2-[[5- (hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)-1-
       oxopentyl]amino]butyl]amino]-N-[2-methyl-1-[[(2-
       pyridinylmethyl)amino]carbonyl]butyl]-, [3aS-[3a alpha, 4 beta
       (1R*,2R*,3R*),6 alpha]]-) sustained a more than 5-fold increase in serum
       concentration at all time points relative to the benchmark structure.
       The remaining two had serum concentrations at least equal to the
       benchmark, suggestive of improved resistance to clearance. One
       (L-idonamide,6-cyclohexyl-2,5,6-trideoxy-5-[[2-[[5-(hexahydro-2-o- x
       o-1H- thieno-[3,4-d]imidazol-4-yl)pentyl]thio]benzoyl]amino]-2-(1-
       methylethyl)-N-[2-methyl-1-[[(2-pyridinyl-
       methyl)amino]carbonyl]butyl]-, [3aS-[3a alpha, 4 beta(1R*,2R*),6a
       alpha]]-) was prepared as a complex with the biotin-binding protein
       avidin. Avidin may resemble an endogenous serum biotin carrier
       protein.(ABSTRACT TRUNCATED AT 400 WORDS)
 DE    Animal  Biological Availability  Biotin/*PHARMACOKINETICS  Drug
       Synergism  Human  HIV Protease Inhibitors/CHEMICAL
       SYNTHESIS/*PHARMACOKINETICS  HIV-1/*DRUG EFFECTS/ENZYMOLOGY  Male  Rats
       Rats, Sprague-Dawley  Receptors, Growth Factor/METABOLISM  Tumor Cells,
       Cultured  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).