The Chemistry and Synthesis Center (CSC) of the National Heart, Lung, and Blood Institute (NHLBI) provides IRP scientists with targeted imaging probes and chemical tools that help accelerate cell based assays, in vivo imaging studies, and translational research leading to better disease diagnosis and therapy. It comprises a core synthesis facility dedicated to the preparation of imaging probes, including radiolabeling for PET and SPECT applications, and a research component dedicated to the discovery of new imaging approaches and compositions.
- PROTACS - Proteolysis-targeting chimeras (PROTACS) are a small molecule based approach to knocking out a specific protein. Similar to siRNA or CRISPR-Cas9, a PROTAC can degrade a target protein via the native proteasomal machinery, without genetic modification to the cell. CSC works with PIs to collaboratively design and synthesize PROTACS to degrade specific proteins of interest.
- Metabolomic feature identification - The presence and amount of a specific metabolite in cells, biofluids, tissues, or organisms can be directly reflective of biochemical processes occurring in a biological system in response to its environment. In a typical untargeted metabolomics experiment, hundreds to thousands of features are identified by HPLC or GC retention time – MS m/z pairs (features). The CSC can identify putative features and confirm by preparing noncommercially available authentic standards (and labeled analogs). We don’t perform the metabolism studies.
- Fragment based lead optimization by NMR- NMR techniques are employed to generate high affinity ligands by identifying, optimizing and linking two small organic molecules to bind at proximal subsites of the protein. “SAR by NMR” is an approach where structure-activity relationships (SAR) are obtained by NMR.
- Targeted nanoparticles (Fe, Au, C) - Targeted nanoparticles have multiple uses in fluorescent and MRI imaging. The ability to manipulate the tissue uptake and biodistribution of these moieties relies on a highly tailorable and fully accessible surface. The introduction of various functional groups can be used to solubilize, reduce aggregation, and attach drugs or biomolecules to the nanoparticle. The CSC has prepared targeted Fe and Au nanoparticles as well as fluorescent nanodiamonds.
- Peptide optimization and multimerization - We have expertise in peptide design, and use solid phase peptide synthesis (SPPS) to investigate SAR of sequences of interest to increase potency, metabolic stability, and water solubility. We can synthesize multimers to increase potency based on avidity. In addition, we also offer solution phase synthesis of complex peptides where SPPS is not effective. We have experience in derivatization of peptides with reporter moieties, e.g. dyes, macrocycles for chelation and precursors for radiolabeling.
- Small Molecule Synthesis - Medicinal chemistry leads and potential drugs from the literature are widely used as chemical tools for studying biological functions. We routinely synthesize compounds from the literature, perform hit to lead optimization for screening efforts, and derivatize heterocycles with fluorescent or Raman tags or chelates.
- Fluorescent probes - Fluorescence remains the premier approach to monitoring occurrences on a cellular level, with approaches that grow ever more sophisticated. CSC synthesizes custom fluorescent and light-activated probes, including fluorophore-labeled peptides, fluorescent or photoactivated drugs, fluorescent versions of native biological small molecules, and other literature-reported fluorescent tools, for biological research.
- Hyperpolarized probes for MRI - Hyperpolarized contrast agents can be used to track metabolism and monitor characteristics of the tissue microenvironment by MRI. NMR hyperpolarization techniques enable a wide range of functional MR imaging from the lungs to metabolic imaging of cancer, and are ideal for the imaging of minor changes in small molecules such as fumarate, choline, and glutamine. The CSC routinely prepares isotopically labeled metabolites for the use in these studies.
- Lanthanide chelates for MRI - The unique paramagnetic properties of the lanthanide ions render them useful as magnetic resonance imaging (MRI) contrast agents and paramagnetic relaxation enhancement or pseudo-contact shift (PCS) tags in structural NMR applications. CSC has experience in the generation of lanthanide(III)-chelates and adducts.
- 89Zr and 18F PET probes - Positron emission tomography (PET) provides information not only on biochemical, physiological and pharmacological processes but also offers the opportunity to study pharmacokinetics, metabolism, and mechanisms of action of novel and established drugs. We work with fluorine-18 and zirconium-89 PET isotopes to develop new probes or produce already existing probes. More than 40 different probes have been provided to the NIH investigators with an average of 150 production batches/year.
- Liposomes, protein purification, and antibody digestion - Large molecule expertise at IPDC includes conjugation of proteins and peptides, antibody digestion, and protein purification. Antibodies and antibody fragments can be modified with chelating groups and fluorescent dyes. Encapsulation of drugs in liposomes can improve delivery and solubility. Liposome formulations can be prepared and extruded on a small scale.
A PI with a need for chemistry support may contact the Director of the Chemistry and Synthesis Center (Rolf Swenson) to discuss the research. Typically the PI and the CSC develop a 2-3 page proposal describing the research and compound synthesis requested from the CSC. The proposal is then approved by the Scientific Director of the PIs institute and then by the CSC steering committee, which evaluates chemical feasibility. The CSC does not support extramural researchers, unless they are collaborators of an intramural PI. For routine compound synthesis we also assist PIs in cost-effective outsourcing of chemical synthesis.
Chemistry and Synthesis Center fees: 25% are paid for by the Intramural NIH Institutes as a form of school tax. The remaining 75% of the fees is charged to the Institute based on the hours worked on the project. The billing doesn’t start until the following calendar year and is spread over three years.