Lab Sections and Chiefs
Paul Kovac, Ph.D., Dr. h.c.
Chemical Biology in Signaling Section
Ross Cheloha, Ph.D., Stadtman Tenure-Track Investigator
Molecular Recognition Section
Kenneth A. Jacobson, Ph.D., John W. Daly Distinguished Scientist
Molecular Signaling Section
Jürgen Wess, Ph.D.
Natural Products Chemistry Section
Carole A. Bewley, Ph.D.
Synthetic Bioactive Molecules Section
Daniel Appella, Ph.D.
Paul Kovac, Ph.D., Dr. h.c., Section Chief
The Section on Carbohydrates furthers the development of conjugate vaccines from synthetic and bacterial 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 and fragments of bacterial lipopolysaccharides 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 protective 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 bacterial diseases, e.g. cholera and anthrax.
Ross Cheloha, Ph.D., Stadtman Tenure-Track Investigator, Acting Section Chief
The Chemical Biology in Signaling Section develops new methods and tools to probe and modulate the function of cell surface proteins. Towards this end we devise new chemical approaches to connect synthetic molecules and recombinantly expressed proteins to create hybrid conjugates with unique properties. We specifically focus on the use of single domain antibodies (nanobodies), which possess several attractive qualities. The versatility of nanobody-small molecule conjugates provides an avenue for chemical creativity in optimizing the characteristics of small molecules/nanobodies used and the chemistry used for linkage. The use of nanobodies, which enables targeting of a wide array of cell surface proteins, allows us to select the identity of the cell surface receptor(s) based on chemical and biological considerations. These factors allow us to target receptors of substantial biological interest, such as G protein-coupled receptors (GPCRs), which constitute the target of >30% of approved medicines. Researchers in this section use nanobody-small molecule conjugates as mechanistic probes to study GPCR pharmacology. Focus is placed on GPCRs such as PTHR1, GLP1R, and adenosine receptors, which are important for diseases such as osteoporosis, diabetes, and inflammation. Nanobodies are also used as aids in medicinal chemistry campaigns to identify new ligands for these receptors. New synthetic methods from the fields of organic and peptide chemistry are under development to expand the application of nanobodies.
The Section on Molecular Recognition studies the structure and pharmacology of cell surface receptors. Receptor structures are determined by X-ray crystallography and my modeling to guide small molecule design. 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. We also explore the indirect modulation of receptor action by targeting allosteric sites and enzymes associated with the action of purines. Substances invented in the Section have proven useful 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. We are examining the structure activity relationship of novel agonists and antagonists of both ARs and P2Y receptors in various disease models. Some of these receptor ligands have potential for treating diseases of the nervous, immune, musculoskeletal, renal, endocrine and cardiovascular systems. Selective AR agonists IB-MECA and Cl-IB-MECA invented in our Section are in clinical trials for autoimmune inflammatory diseases, such as rheumatoid arthritis and psoriasis, and liver cancer. Recently, chronic neuropathic pain was shown to be a new target for selective AR agonists. Certain P2X receptor agonists invented in our section are proving efficacious in models of heart failure.
Jürgen Wess, Ph.D., Section Chief
The Molecular Signaling Section studies G protein-coupled receptors (GPCRs). These receptors are of utmost importance in biology and medicine — ~ 30-40 % of drugs in current clinical use act on specific GPCRs. Research in this area focuses on the molecular basis of GPCR activation and elucidating GPCR structure and function, with particular focus on the muscarinic receptor family (M1-M5 receptors). Currently, a major aim of the section is to identify GPCR signaling pathways that play critical roles in the regulation of glucose and energy homeostasis, as well as other physiological functions. This work involves the generation and phenotypic analysis of a large number of GPCR mutant mice. In particular, the cell-type specific expression of muscarinic receptor-based designer GPCRs endowed with different coupling properties makes it possible to dissect metabolically relevant GPCR signaling pathways in a temporally and spatially controlled fashion in vivo. Since beta-arrestins (beta-arrestin-1 and -2) are key regulators of essentially all GPCRs, the section is also using gene targeting approaches to explore the physiological roles of these GPCR-associated proteins in metabolically relevant tissues in mice. The ultimate goal of this research is to identify novel targets for the treatment of type 2 diabetes and related metabolic disorders.
Carole A. Bewley, Ph.D., Section Chief
The Section on Natural Products Chemistry conducts interdisciplinary research aimed at the discovery, design or synthesis of diverse molecules important to the study or treatment of infectious diseases. Our research aims to discover new antibiotics, with the ultimate goal of identifying their bacterial targets and determining the structural and chemical basis for their mechanisms of action. Discovery efforts in our group start with natural products, also known as secondary metabolites, as these are the complex small molecules that make up our current arsenal of antibiotics. We also focus on developing small molecule and protein inhibitors that prevent viral infection, and chemical probes that help reveal individual steps along the path to viral infection. One hallmark of enveloped viruses such as HIV and HCV is the presence of a dense carbohydrate shield that covers the viral spike proteins. This so-called glycan shield can be targeted by carbohydrate binding proteins known as lectins, some of which block viral infection. We perform structural and functional studies involving viruses, glycans and lectins to determine the mechanisms by which carbohydrate-mediated inhibition takes place.
Daniel Appella, Ph.D., Section Chief
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 PNA research is to develop this backbone as a scaffold for the multivalent display of small molecules that bind to protein receptors. These types of scaffolds allow high resolution multivalent effects to be explored at cellular surfaces. Other research focuses on developing a small molecule inhibitor for the nucleocapsid protein 7 (NCp7) of HIV. This HIV target is a small zinc-finger that binds to HIV RNA, and interfering with the normal functions of NCp7 may lead to new HIV therapeutics. We are synthesizing and studying a specific class of mercaptobenzamide molecules that inactivate NCp7.