U.S. Department of Health and Human Services

Laboratory of Bioorganic Chemistry

Kenneth A. Jacobson, Ph.D., Chief

Laboratories

Carbohydrates Section

Paul Kovac, Ph.D.

The Section on Carbohydrates Section furthers the development of conjugate vaccines from synthetic carbohydrate antigens. The ultimate goal is to develop reliable protocols for the preparation of neoglycoconjugates, which could become substitutes for traditional vaccines. Traditional vaccines are based on antigens present in e.g. attenuated cells and are often pyrogenic or have other undesirable effects. Section scientists use synthetic oligosaccharides that mimic the structure of polysaccharides present on the surface of bacterial pathogens as antigenic components of immunogens. Studies examine the effects of variables such as the size of the carbohydrate antigen, type of linker, linking chemistry, and type of carrier on immunogenicity and protctive capacity. The findings are of general utility in synthetic vaccine preparation. Scientists in the section use a well-established approach to study the interaction of carbohydrate antigens and antibodies. The section’s research has revealed a great deal of detailed information about binding on the molecular level. Following the same concept, current work focuses on the development of synthetic vaccines for cholera and anthrax.

Molecular Recognition Section

Kenneth A. Jacobson, Ph.D.

The Section on Molecular Recognition studies the structure and pharmacology of cell surface receptors. We design and synthesize new drug molecules that act as agonists or antagonists of G protein-coupled receptors (GPCRs). Research currently focuses on receptors for purines, encompassing both adenosine receptors (ARs) and P2 receptors. P2 receptors include both P2Y receptors, which are GPCRs, and P2X ligand-gated ion channels. Substances invented in the Section have proven useful as as potent and selective pharmacological probes that act through adenosine and P2 receptors. Many pharmacology laboratories are using these probes to define the role of the receptors in the body. Some of these receptor ligands have potential for treating diseases of the nervous, immune, musculoskeletal, renal, endocrine and cardiovascular systems.

Various approaches are used in drug design, including a "functionalized congener approach" that has provided high affinity fluorescent probes for GPCRs. We synthesize novel ligands (small molecules) for these receptors by applying classical synthetic approaches and rational methods based on molecular modeling and template design. Receptors are computer-modeled by homology to related GPCRs, and the models and hypotheses for ligand docking are tested and refined using site-directed mutagenesis of the receptor proteins. Reengineering of the receptor binding site is a means to achieve the protective effects of AR activation through "neoceptors."

A3AR agonists IB-MECA and Cl-IB-MECA invented in our Section are in clinical trials for autoimmune inflammatory diseases and liver cancer. Recently, chronic neuropathic pain was shown to be a new target for selective A3AR agonists. We are examining the structure activity relationship of novel agonists and antagonists of both ARs and P2Y receptors in various disease models. P2X4 receptor agonists invented in our section are proving efficacious in models of heart failure.

Molecular Signaling Section

Jürgen Wess, Ph.D.

The Molecular Signaling Section studies G protein-coupled receptors (GPCRs). These receptors are very important in biology and in medicine—approximately 30-40 percent of drugs in current clinical use act on specific GPCRs. Research in this area focuses on the molecular basis of GPCR activation and elucidating their function and structure. Specific projects use different molecular genetic and biochemical strategies to determine how GPCRs interact with G proteins and other GPCR-associated proteins, identify conformational changes induced in the receptor protein, and examine the structural basis and functional relevance of GPCR dimerization.  Research activities also include the generation and analysis of GPCR mutant mice. Section scientists use these mice to explore the roles of distinct GPCR signaling pathways in the regulation of energy and glucose homeostasis, as well as other physiological functions.  Work in this area aims to elucidate the physiological roles of the individual muscarinic receptor subtypes.​

Natural Products Chemistry Section

Carole A. Bewley, Ph.D.

The Section on Natural Products conducts multi-faceted studies of biologically active natural products (also known as secondary metabolites), designs peptide and protein inhibitors and probes of HIV-1 entry, and discovers and fully characterizes novel carbohydrate-binding proteins from understudied sources. Scientists working in this section subscribe to the notion that natural products represent an ideal starting point for identifying new inhibitors of macromolecular receptors and biological processes because of  evolutionary pressure to effect specific biological processes. Specific projects include elucidating the structure of natural products that inhibit mycobacterial enzymes and HIV-1 membrane fusion and using bioassays and biophysical techniques to determine their mechanism of action. Work in the area of peptide and protein inhibitors of HIV-1 entry includes engineering stable trimeric gp41 N-helices as inhibitors and immunogens, chemical synthesis of post-translationally modified coreceptor-derived peptides and analogs, and high resolution structural studies. Research in the section also aims to discover novel carbohydrate-binding proteins. We conduct comprehensive studies of carbohydrate specificity and recognition for these proteins.​

Synthetic Bioactive Molecules Section

Daniel Appella, Ph.D.

The Synthetic Bioactive Molecules Section uses synthetic organic chemistry to create new molecules with unique biological activities. Our scientists also use a large amount of molecular modeling and biophysical techniques to study the molecules we make. Specific projects have the potential to evolve into a new strategy for diagnosing or treating a disease.  We also have several collaborations within the NIH and with other institutions to study the biological effects of our molecules in vivo. Specific projects focus on peptide nucleic acids (PNAs), which are very flexible molecules that bind to complementary DNA and RNA with high affinity and sequence specificity. Section researchers are exploring ways to alter these molecules to provide the basis for design of PNA-based sensors. Other modifications could significantly enhance their binding properties to DNA and RNA and improve many of the diagnostic techniques that rely on PNA. Another area of scientific interest is the design and synthesis of organic molecules that can selectively recognize folded RNA structures. This research aims to create a new class of molecules that bind with high affinity and specificity to folded RNAs, which are underutilized as a potential target for drug development.  Other research focuses on the protein p53, an important tumor suppressor. About half of human tumors have mutant p53 protein, which enables continued tumor growth. Section scientists are developing new methods to restore the normal functions to mutant p53, which could lead to new therapies for cancer.