Solubilization of a tripeptide HIV protease inhibitor using a combination of ionization and complexation with chemically modified cyclodextrins.
Solubilization of a tripeptide HIV protease inhibitor using a combination of ionization and complexation with chemically modified cyclodextrins.
复制标题
使用电离和与化学修饰的环糊精络合的组合来溶解三肽 HIV 蛋白酶抑制剂。
DOI：
10.1002/jps.2600830814
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发表时间：
1994
影响因子：
3.8
通讯作者：
Anderson,BD
中科院分区：
文献类型：
--
作者：
Johnson,MD;Hoesterey,BL;Anderson,BD
Kynostatin (KNI-272), an experimental HIV protease inhibitor, is currently undergoing preclinical testing for the treatment of AIDS. This transition state mimetic tripeptide exhibits extremely low aqueous solubility (4μg/mL) making target concentrations (5-50 mg/mL) for parenteral solution formulations difficult to achieve. The presence of an ionizable (5-isoquinolinyloxy)acetyl moiety makes solubilization via pH adjustment possible, but a solubility > 5 mg/mL requires an adjustment in pH below 2.0, which would be physiologically unacceptable. This study examines and compares two approaches for solubilizing kynostatin: (1) inclusion complex formation at chemically distincthydrophobic binding sites using (2-hydroxypropyl)-β-cyclodextrin (HPCD) and a sulfobutyl ether derivative of β-cyclodextrin (β-CD-SBE) and (2) a combined strategy utilizing ionization of the isoquinoline moiety coupled with inclusion complex formation at the remaining binding site(s). Macroscopic binding constants determined from solubility profiles as a function of pH and HPCD concentration have been compared with the microscopic binding constant for formation of the isoquinoline-HPCD inclusion complex determined by UV difference spectroscopy to examine the independence of binding domains within KNI-272. As demonstrated in this report, combination strategies tailored to the properties of different domains within the molecule may be highly effective in solubilizing compounds such as poorly soluble peptides.
