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HIV protease inhibitors: structure-activity relationship of water-soluble peptidomimetic compounds with potent antiviral activity.
Thaisrivongs S; Chong KT; Ruwart MJ; Yancey MF; Upjohn Laboratories, The
December 30, 1995
Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;:128.

Objective: to design peptidomimetic inhibitors of HIV protease with improved physical properties, maintenance of potent antiviral activity, and increased blood levels of inhibitors in vivo as potential parenteral therapeutic agents for the treatment of HIV infection. Methods: Peptidomimetic inhibitors were prepared incorporating strategically placed water-solubilizing groups. Enzyme inhibitory activity was assayed using the octapeptide substrate corresponding to the cleavage site of the gag polyprotein. For antiviral activity, human PBMC were infected with HIV-1IIIB at 0.003 multiplicity of infection, maintained in the absence or presence of test compounds for 7 days, and the effect on p24 production of the harvested supernatants was measured by an ELISA. Time-course serum concentrations of test compounds after intravenous administration to rats were analyzed by quantitative analytical HPLC method. Results: From this study, inhibitors with potent antiviral activity (IC90 20 nM) in HIV-1IIIB- infected PBMC, with high water solubility (greater than 10 mg/mL at pH7), and with prolonged blood levels in rats after intravenous administration (greater than 100 ng/mL for more than 2 hours at 2 mg/kg dose) were identified. Discussion and Conclusion: Evaluation of a series of peptidomimetic inhibitors resulted in highly water soluble compounds that exhibited potent antiviral activity in vitro and prolonged blood levels in vivo after intravenous administration. The availability of these compounds offers the opportunity to consider potential parenteral formulation of these inhibitors for the treatment of HIV infection.

Cells, Cultured Copper/*PHARMACOLOGY Human HIV Core Protein p24 HIV Protease Inhibitors/*PHARMACOLOGY HIV-1/*ENZYMOLOGY/PHYSIOLOGY Indicators and Reagents Phenanthrolines/PHARMACOLOGY Virus Replication/*DRUG EFFECTS ABSTRACT