12-methoxydodecanoic acid (12-MO) is a heteroatom fatty acid analog of myristic acid that exhibits potent anti-HIV activity and 12MO is therefore a biologically active fatty acid. Diacylated phosphatidylcholine containing 12MO in both the sn-1 and sn-2 position of the glycerobackbone was synthesized (and this anti-HIV compound is denoted as AC2) is more potent and less toxic than 12MO. In three different anti-HIV assays (i.e., syncytial assays, reverse transcriptase assays, T-Cell cytopathic assays), AC2 exhibits approximately 4 fold increased activity compared to the free fatty acid 12MO. AC2 contains 2 equivalents of AC2 and this 4 fold increased activity exceeds the expected 2 fold increase activity if the cellular availability and cellular disposition of free 12MO is identical to 12MO tethered to the phospholipid molecule. In addition, we have demonstrated potent synergism with AC2 and AZT in T-cells. The primary objective of this work is to perform a comprehensive structure activity relationship (SAR) of single chain and double chain phospholipids, which contain biologically active compounds as alkyl chains, regarding anti-HIV activity in both T-cells and macrophages. Thus single and double chain phospholipid analogs containing 12MO will be prepared with different lipid headgroups: phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), and phosphatidic acid (PA). The metabolic rate of diacylated and monoacylated phospholipids bearing biologically active fatty acids will be determined in human T-cells and macrophages. this metabolite information is critical for designing heteroatom-fatty- acids and phospholipids as drugs for AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033031-02
Application #
2067999
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1992-12-01
Project End
1995-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Purdue University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Liu, H; Cohen, D E; Pidgeon, C (1997) Single step purification of rat liver aldolase using immobilized artificial membrane chromatography. J Chromatogr B Biomed Sci Appl 703:53-62
Bernal, C; Pidgeon, C (1996) Affinity purification of phospholipase A2 on immobilized artificial membranes containing and lacking the glycerol backbone. J Chromatogr A 731:139-51
Ong, S; Liu, H; Pidgeon, C (1996) Immobilized-artificial-membrane chromatography: measurements of membrane partition coefficient and predicting drug membrane permeability. J Chromatogr A 728:113-28
Pidgeon, C; Cai, S J; Bernal, C (1996) Mobile phase effects on membrane protein elution during immobilized artificial membrane chromatography. J Chromatogr A 721:213-30
Ong, S; Liu, H; Qiu, X et al. (1995) Membrane partition coefficients chromatographically measured using immobilized artificial membrane surfaces. Anal Chem 67:755-62
Cai, S J; McAndrew, R S; Leonard, B P et al. (1995) Rapid purification of cotton seed membrane-bound N-acylphosphatidylethanolamine synthase by immobilized artificial membrane chromatography. J Chromatogr A 696:49-62
Liu, H; Ong, S; Glunz, L et al. (1995) Predicting drug-membrane interactions by HPLC: structural requirements of chromatographic surfaces. Anal Chem 67:3550-7
Pidgeon, C; Ong, S; Liu, H et al. (1995) IAM chromatography: an in vitro screen for predicting drug membrane permeability. J Med Chem 38:590-4
Ong, S; Pidgeon, C (1995) Thermodynamics of solute partitioning into immobilized artificial membranes. Anal Chem 67:2119-28
Qiu, X; Pidgeon, C (1994) Membrane properties of antiviral phospholipids containing heteroatoms in the acyl chains. Biochemistry 33:960-72

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