The self-organization of supramolecular systems is commonplace in vivo. In marked contrast, the design and synthesis of simple, artificial self- assembling systems in vitro that exhibit biologically-relevant activity remains a rarity. We have decided to explore the general area of self- assembling artificial enzymes, with special emphasis on the creation of heme-containing protein mimics. The following areas will be investigated: (a) Hemoglobin mimics - stage 1. We have achieved a template-driven self- assembly of a porphyrin-containing supramolecular complex. This species contains a porphyrin moiety ensconced within the protective cavity of two cyclodextrin components. We plan to investigate the ability of related complexes to reversibly bind oxygen in organic solvents. The half-life of the oxygenated species, as well as the affinity (i.e. oxygen partial pressure at which the heme moiety is half saturated) that these complexes exhibit for oxygen will be determined. (b) Hemoglobin mimics - stage 2. At this stage, an axial ligand will be covalently appended to the supramolecular complex itself, thereby eliminating the requirement for exogeneous ligand. (c) Hemoglobin mimics - stage 3. An appropriately substituted heme- containing supramolecular complex will be incorporated into a liposome. Liposomal-encapsulated species are not only nonimmunogenic, but also exhibit enhanced circulatory lifetime relative to their nonencapsulated counterparts. (d) Cytochrome P-450 mimics - stage 1. We will investigate the ability of Mn.porphyrin-containing water-soluble supramolecular complexes to catalyze the oxidation of organic substrates in the presence of an oxygen donor, such as hypochlorite. The oxidation rate and stability of these complexes will be compared to those reported by other investigators. (e) Cytochrome P-450 mimics - stage 2. Dioxygen will be employed as the ultimate source of the oxygen atom that is inserted into the substrate. To effect the reductive activation of the metalloporphyrin-bound dioxygen moiety, a conduit to deliver electrons to the oxygen-binding site will be incorporated into the supramolecular complex. The self-assembly process represents a powerful synthetic alternative to the conventional stepwise covalent bond approach in the construction of artificial supramolecular systems. As exemplified by this proposal, structurally well-defined multicomponent entities may ultimately prove useful as analogs of hemoglobin (i.e. an artificial blood) and other crucial protein-based biologically active species.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL047346-01
Application #
3366542
Study Section
Metallobiochemistry Study Section (BMT)
Project Start
1992-02-01
Project End
1995-01-31
Budget Start
1992-02-01
Budget End
1993-01-31
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Type
Schools of Arts and Sciences
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260