Designed ankyrin repeat proteins for detecting prostate-specific antigen expression .

Late-stage prostate cancer often acquires resistance to conventional chemotherapies and transforms into a hormone-refractory, drug-resistant, and non-curative disease. Developing non-invasive tools to detect the biochemical changes that correlate with drug efficacy and reveal the onset of drug resistance would have important ramifications in managing the treatment regimen for individual patients. Here, we report the selection of new Designed Ankyrin Repeat Proteins (DARPins) that show high affinity toward prostate-specific antigen (PSA), a biomarker used in clinical monitoring of prostate cancer.

Charting the Chemical and Mechanistic Scope of Light-Triggered Protein Ligation.

The creation of discrete, covalent bonds between a protein and a functional molecule like a drug, fluorophore, or radiolabeled complex is essential for making state-of-the-art tools that find applications in basic science and clinical medicine. Photochemistry offers a unique set of reactive groups that hold potential for the synthesis of protein conjugates. Previous studies have demonstrated that photoactivatable desferrioxamine B (DFO) derivatives featuring a para-substituted aryl azide (ArN) can be used to produce viable zirconium-89-radiolabeled monoclonal antibodies (Zr-mAbs) for applications in noninvasive diagnostic positron emission tomography (PET) imaging of cancers.

Synthesis of photoactivable oligosaccharide derivatives from 1,2-cyclic carbamate building blocks and study of their interaction with carbohydrate-binding proteins.

Despite the broad occurrence of carbohydrate-protein interactions in biology, the low binding affinities of such interactions hamper the characterization of carbohydrate binding sites in the absence of three-dimensional structural models. To allow the identification of proteins interacting with specific carbohydrate epitopes, we have developed new photoactivable oligosaccharide probes. Oligosaccharides containing the 1,2-cyclic carbamate group were attached to building blocks with a primary amino group to yield the corresponding urea derivatives.

Expanding the Chemistry Palette for Radiotracer Synthesis.

The synthesis, characterisation and application of radiolabelled compounds for use in diagnostic and therapeutic medicine requires a diverse skill set. This article highlights a selection of our ongoing projects that aim to provide new synthetic methods and radiochemical tools for building molecular imaging agents with various radionuclides.

Synthesis of Morpholine-Based Analogues of (-)-Zampanolide and Their Biological Activity.

We describe the convergent synthesis of three prototypical examples of a new class of analogues of the complex, cytotoxic marine macrolide (-)-zampanolide that incorporate an embedded N-substituted morpholine moiety in place of the natural tetrahydropyran ring. The final construction of the macrolactone core was based on a high-yielding intramolecular HWE olefination, while the hemiaminal-linked side chain was elaborated through a stereoselective, BINAL-H-mediated addition of (Z,E)-sorbamide to a macrocyclic aldehyde precursor. The synthesis of the common functionalized morpholine building block involved two consecutive epoxide openings with tosylamide and the product of the first opening reaction, respectively, as nucleophiles.

Photochemical Reactions in the Synthesis of Protein-Drug Conjugates.

The ability to modify biologically active molecules such as antibodies with drug molecules, fluorophores or radionuclides is crucial in drug discovery and target identification. Classic chemistry used for protein functionalisation relies almost exclusively on thermochemically mediated reactions. Our recent experiments have begun to explore the use of photochemistry to effect rapid and efficient protein functionalisation.

Synthesis and Photochemical Studies on Gallium and Indium Complexes of DTPA-PEG-ArN for Radiolabeling Antibodies.

Photochemistry is a rich source of inspiration for developing alternative methods to functionalize proteins with drug molecules, fluorophores, and radioactive probes. Here, we report the synthesis and photochemical reactivity of a modified diethylenediamine pentaacetic acid chelate that was derivatized with a light-responsive aryl azide group (DTPA-PEG-ArN, compound ). The corresponding nonradioactive and radioactive Ga and In complexes of DTPA-PEG-ArN were synthesized and their physical and photochemical properties were studied to evaluate the potential of employing this ligand system in the photochemical synthesis of radiolabeled antibodies.

Photoradiosynthesis of Ga-Labeled HBED-CC-Azepin-MetMAb for Immuno-PET of c-MET Receptors.

In an alternative approach for radiotracer design, a photoactivatable HBED-CC-PEG-ArN chelate was synthesized and photoconjugated to the anti-c-MET antibody MetMAb (onartuzumab). Photoconjugation gave the functionalized protein HBED-CC-azepin-MetMAb with a photochemical conversion of 18.5 ± 0.