Disease relevance of KNI 272

• Additionally, the modified PR is inhibited completely by the HIV-1 PR-specific inhibitor KNI-272 at concentrations where wild-type RSV PR is unaffected [1].
• As tested in target CD4+ ATH8 cells, the 50% inhibitory concentrations of KNI-227 against HIV type 1 LAI (HIV-1LAI), HIV-1RF, HIV-1MN, and HIV-2ROD were 0.1, 0.02, 0.03, and 0.1 microM, respectively, while those of KNI-272 were 0.1, 0.02, 0.04, and 0.1 microM, respectively [2].
• The infectivity (50% tissue culture infective dose per milliliter) of the viral particles from KNI-272-treated cells was 10(6)-fold lower than that of control particles and did not significantly increase over the 48 h after the inhibitor was removed, despite the apparent return of protease function in a subset of these virions [3].
• Plasma and CSF were sampled over 24 h after the administration of an intravenous dose of 50 mg of KNI-272 per kg of body weight (approximately 1,000 mg/m2) to three nonhuman primates [4].
• The pharmacokinetics, toxicity, and activity of KNI-272, a transition state inhibitor of HIV-1 protease, was assessed in a phase I trial [5].

High impact information on KNI 272

• Moreover, by using selective cytochrome P-450 inhibitors and recombinant human CYP3A4 fractions, KNI-272 was determined to be metabolized mainly by the CYP3A isoform [6].
• Metabolic characterization of a tripeptide human immunodeficiency virus type 1 protease inhibitor, KNI-272, in rat liver microsomes [6].
• Moreover, in tissue distribution studies, KNI-272 distributed highly to the liver, kidney, and small intestine in vivo [6].
• The pharmacokinetics of KNI-272 in children were characterized by rapid elimination (clearance, 276 ml/min/m2; terminal half-life, 0.44 h), limited (12%) and apparently saturable bioavailability, and limited distribution (volume of distribution at steady state, 0.11 liter/kg) [4].
• Pharmacokinetics of the protease inhibitor KNI-272 in plasma and cerebrospinal fluid in nonhuman primates after intravenous dosing and in human immunodeficiency virus-infected children after intravenous and oral dosing [4].

Chemical compound and disease context of KNI 272

• The aspartyl dyad of free HIV-1 protease has apparent pK(a)s of approximately 3 and approximately 6, but recent NMR studies indicate that the aspartyl dyad is fixed in the doubly protonated form over a wide pH range when cyclic urea inhibitors are bound, and in the monoprotonated form when the inhibitor KNI-272 is bound [7].
• Structure of HIV-1 protease with KNI-272, a tight-binding transition-state analog containing allophenylnorstatine [8].
• Co-infection of MT-2 cells with HIV-1SUM13 carrying the RT mutations and HIV-1SUM431 carrying the mutations in the protease also generated HIV-1 with both sets of mutations when cultured with AZT and KNI-272 [9].
• To improve the low water-solubility of HIV protease inhibitors, we synthesized water-soluble prodrugs of KNI-272 and KNI-279 which are potent HIV-1 protease inhibitors consisting of an Apns-Thz core structure (Apns; allophenylnorstatine, Thz; thiazolidine-4-carboxylic acid) as an inhibitory machinery [10].

Biological context of KNI 272

• The pharmacokinetics of KNI-272 were also studied in 18 children (9 males and 9 females; median age, 9.4 years) enrolled in a phase I trial of four dose levels of KNI-272 (100, 200, 330, and 500 mg/m2 per dose given four times daily) [4].
• Protein binding of human immunodeficiency virus protease inhibitor KNI-272 and alteration of its in vitro antiretroviral activity in the presence of high concentrations of proteins [11].
• The targets of a protease inhibitor, KNI-272, in the HIV-1 life cycle were investigated in this study [12].
• RESULTS: The three-dimensional crystal structure of KNI-272 bound to HIV PR has been determined to 2.0 A resolution and used to analyze structure-activity data and drug resistance for the Arg8-->Gln and ILe84-->Val mutations in HIV PR [8].
• The plasma kinetics of KNI-272 were dose-independent within a dose range of 1.0 to 10.0 mg/kg [13].

Anatomical context of KNI 272

• KNI-272 was metabolized in the rat liver microsomes, and five metabolites were found [6].
• Doughnut-shaped immature particles were observed in the extracellular space of the cells, and disrupted semicircular shaped particles were also seen at the higher concentration of KNI-272 [12].
• These results suggest that KNI-272 is stable and not extensively hydrolysed in the gut after oral administration, that the dissolution process into GI fluids is important for the BA of KNI-272, and that the most appropriate absorption site of KNI-272 in dogs is the duodenum [14].

Associations of KNI 272 with other chemical compounds

• Following resuspension of the particles in medium free of the inhibitor, some gag polyprotein processing was detected in particles produced from the KNI-272-treated cells, but not from the saquinavir-treated cells within the first 3 h [3].
• The modified Scatchard plots of KNI-272 binding to AAG and HSA both showed biphasic curves, and the KNI-272 binding sites at low concentration range on AAG and HSA disappeared with the addition of disopyramide and warfarin, respectively [15].

Gene context of KNI 272

• Detailed studies of the protein binding of KNI-272 suggest that in human plasma binding occurs predominantly to alpha 1-acid glycoprotein and that KNI-272 is probably extensively (approximately 98 to 99%) protein bound at concentrations likely to be achieved in the circulation [11].
• To improve the low water-solubility of HIV-1 protease inhibitors KNI-272, -279 and -727, we previously reported the water-soluble prodrugs of these inhibitors based on O-->N intramolecular acyl migration reaction [16].
• The binding characteristics of KNI-272, a potent and selective human immunodeficiency virus (HIV) protease inhibitor, were evaluated in rat and human plasma, and in solutions of human alpha 1-acid glycoprotein (AAG) and human serum albumin (HSA) [15].

Analytical, diagnostic and therapeutic context of KNI 272

• We studied the pharmacokinetics of KNI-272 in the plasma and cerebrospinal fluid (CSF) of a nonhuman primate model and after intravenous and oral administration to children with HIV infection [4].
• Thus, higher levels of KNI-272 in plasma may be required when this compound undergoes clinical trials relative to those inferred from in vitro data involving the use of 10 to 15% FCS-containing culture media [11].
• KNI-272 is a promising, potent HIV-1 protease inhibitor (K(i) approximately 5 pM), currently undergoing phase 1 clinical trials [17].
• A phase I/II study of the safety and activity of a microsphere formulation of KNI-272 in patients with HIV-1 infection [18].
• Thermodynamic dissection of the binding energetics of KNI-272, a potent HIV-1 protease inhibitor [19].

References