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Scientific Report 2008


Chemistry




Organic, Medicinal, and Biological Chemistry


M.G. Finn, A. Accurso, S. Brown, S.-H. Cho, V. Hong, J. Lau, S. Lee, Y.-H. Lim, S. Presolski

In addition to our work on biological polyvalency and immunology with engineered virus particles, supported by the Skaggs Institute for Chemical Biology, we focus on the development of catalysts and the synthesis of biologically useful structures. Two of these projects are described in the following sections.

Copper-Catalyzed Azide-Alkyne Click Chemistry

We have continued our development of new catalysts and conditions for the copper-catalyzed azide-alkyne cycloaddition reaction, which has become a principal example of click chemistry in the synthesis of possible drugs, dendrimers, polymers, and functionalized surfaces in laboratories around the world. In the past year, using an active but highly air-sensitive catalyst, we developed a convenient electrochemical protocol for performing bioconjugations. This procedure enables investigators who lack sophisticated inert-atmosphere equipment to perform the reaction under demanding conditions. We have also discovered new derivatives of the (benzimidazole-methyl)amine ligands reported last year, which accelerate the copper-catalyzed azide-alkyne cycloaddition reaction to a remarkable degree. A comprehensive picture is rapidly emerging of the types of ligands effective under the diverse conditions in which this cycloaddition reaction is applied.

An important application of click chemistry is the synthesis and modification of polymeric materials. We found that metal adhesives can be formed by the simple application of mixtures of polyvalent azide and alkyne compounds to copper-containing surfaces. By incorporating amino groups to help speed the click reaction, and flexible cross-linking molecules to protect against stress fracturing in the resulting polymers, greatly improved adhesives have been created. Figure 1 illustrates the strength of one of these formulations, which has potential in such applications as protective coatings, electrically conducting junctions, and antifouling agents.

Agents With Activity Against Hepatitis B Viruses: Misdirecting Protein-Protein Interactions

Modulation of protein-protein contacts by small molecules is an attractive strategy for the development of biologically active compounds. In many instances, the target interprotein interaction covers a substantial landscape with high thermodynamic stability. Virus particles rely on the assembly of protein subunits that engage in well-defined protein-protein interactions. However, these interactions are necessarily weak until the late stages of assembly; such cooperativity is necessary to ensure that protein is efficiently used in the multistep construction process.

Viral capsid intermediates are therefore a class of protein-protein interface targets that may be easier for small molecules to affect. We have investigated this possibility for hepatitis B virus (HBV), a pathogen that infects 400 million people worldwide. The antiviral activity of the heteroaryldihydropyrimidine class of compounds has been known for several years. We found that their mechanism of action is the distortion, rather than the inhibition, of the protein assembly process. In a type of molecular jujitsu, these small molecules use the natural interactions of the capsid proteins against the virus, by increasing the energy of protein subunit association and the rate of subunit aggregation. This increase causes the viral proteins to assemble in error-prone fashion, forming large and irregular structures rather than the symmetric particles necessary for the proper function of the virus (Fig. 2).
Fig. 1. Graduate student Vu Hong sits on a 20-L container filled with water, supported by 2 copper plates glued together with an adhesive prepared by graduate student Adrian Accurso.



Fig. 2. Negative-stain electron micrographs of the assembly products of HBV capsid protein induced by different heteroaryldihydropyrimidine derivatives. HBV capsids are typically 35 nm in diameter; the structures shown here are many times that size.



 

M.G. Finn, Ph.D.
Associate Professor



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