Vaccinia virus complement control protein (VCP) has been shown to possess the ability to inhibit both classical and alternative complement pathway activation. The newly found ability of this protein to bind to heparin has been shown in previous studies to result in uptake by mast cells, possibly promoting tissue persistence. It has also been shown to reduce chemotactic migration of leukocytes by blocking chemokine binding. In addition, this study shows that VCP-through its ability to bind to glycosaminoglycans (heparin-like molecules) on the surface of human endothelial cells-is able to block antibody binding to surface major histocompatibility complex class I molecules. Since heparin binding is critical for many functions of this protein, we have attempted to characterize the molecular basis for this interaction. Segments of this protein, generated by genetic engineering of the DNA encoding VCP into the Pichia pastoris expression system, were used to localize the regions with heparin binding activity. These regions were then analyzed to more specifically define their properties for binding. It was found that the number of putative binding sites (K/R-X-K/R), the overall positive charge, and the percentage of positively charged amino acids within the protein were responsible for this interaction.
Cyclopropanation of alkenes can be accomplished catalytically2 or stoichiometrically.3 Catalytic systems typically use a diazo reagent as the carbene source and a metal-containing mediator which forms a postulated metal carbene intermediate. Transfer of the carbene fragment from the metal to an alkene produces the cyclopropane product. Despite the wide variety of catalytic cyclopropanation systems, the putative carbene complex has never been isolated or observed in a catalytic system. This is somewhat surprising since the second category of cyclopropanation reactions involves the stoichiometric reaction of isolated car bene complexes with an alkene to form a cyclopropane. None of the isolated carbene complexes show catalytic cyclopropanation activity. Several years ago Callot demonstrated that rhodium porphyrins catalytically cyclopropanated a variety of alkenes in the presence of ethyl diazoacetate.4 Kodadek and co-workers have expanded this work and have attempted to prepare synthetically useful enantioselective catalysts for the formation of cyclopropanes.5 Their approach has been to use rhodium complexes with optically active porphyrins to induce chirality into the product. A similar approach was used for a variety of non-porphyrin copper catalysts.6 Kodadek has shown that the carbon-bound diazonium complex [(TTP)RhC(H)(C02Et)(N2W is an intermediate in the catalytic cyclopropanation of styrene with ethyl diazoacetate.7•8 In addition, kinetic studies suggest that the formation of a rhodium carbene complex is at least partially rate limiting.8 However, this carbene complex has not been isolated or directly observed. We report herein the use of osmium porphyrins as stereoselective cyclopropanation catalysts using ethyl diazoacetate with a variety of alkenes. In addition, our studies show that an isolable carbene complex ((TTP)Os=CHC02Et) is capable of catalytically and stoichiometrically cyclopropanating styrene. Disciplines Chemistry CommentsReprinted ( (Figure 2). Likewise the B-e bonds are shorter than typical single bonds [1.558 A in B(C 2 H 3 h]. 13 Similar evidence has been offered to support delocalization of the two 1r electrons over the three-membered ring and aromatic character for the BC 2 ring in trimesitylborirene.12 Furthermore, the BC 2 rings in BC 2 H 2 and HBC 2 H 2 are seen to be virtually identical. Thus, the u radical site in BC 2 H 2 has no effect on the delocalized 1r bonding in the BC 2 ring. The photolysis of BC 2 H 2 in the near ultraviolet range indicates a strong absorption band in this region, in agreement with trimesitylborirene.13 The photolysis behavior also provides evidence for delocalized bonding as acetylene and ethylene absorb at shorter wavelengths.The appearance of BC 2 H 2 on diffusion and reaction of B atoms at 18 K in solid argon follows similar behavior for B0 2 • 1 These exothermic reactions proceed without activation energy. The BC 2 H 2 radical is the simplest borirene species yet observed and characterized. Further studies are in progress in this laboratory...
Traumatic spinal cord injury (SCI) claims approximately 10,000 new victims each year in the United States alone. The injury usually strikes those under the age of 30 years, often leading to a lifetime of pain, suffering, and disability. Therapeutic agents targeting spinal cord injury are sorely lacking, and therefore our laboratory endeavored to evaluate the potential therapeutic benefits of immediate post-injury administration of the vaccinia virus complement control protein (VCP). VCP is a multifunctional anti-inflammatory protein that can inhibit both pathways of complement activation and bind heparin. Utilizing a common animal model of contusion SCI, motor function recovery tests, and immunochemical stains, we evaluated the effects of VCP injected into spinal cord tissue following injury. Results demonstrate that VCP administration inhibits macrophage infiltration, reduces spinal cord destruction, and improves hind-limb function, establishing VCP as a strong candidate for further investigation in the treatment of SCI.
The vaccinia virus complement control protein (VCP) possesses multiple modulatory functions. Functioning as a complement inhibitory protein, VCP reduces production of proinflammatory chemotactic factors produced during complement activation. Additionally, VCP binds heparin and heparan sulfate proteoglycans, resulting in added functions shown to block monocyte chemotaxis in vitro. Using an in vivo spinal cord contusive injury model in rats, the inflammation-modulating abilities of VCP were evaluated. The results of both myeloperoxidase assaying and H&E stained section counts of spinal tissue reveal that neutrophil infiltration to the area of the lesion was reduced in animals that received VCP as compared to saline-injected controls.
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