The Search for Low Energy Conformational Families of Small Peptides: Searching for Active Conformations of Small Peptides in the Absence of a Known Receptor

Breast cancer is the most common cancer among women. Tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment, yet many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Therefore, scientists are searching for breast cancer drugs that have different molecular targets. Previous work revealed that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat model systems, interacting with an unknown receptor, while peptides smaller than eight amino acids did not inhibit breast cancer. We have shown that the use of replica exchange molecular dynamics predicts structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. These simulations identified smaller peptide analogs with a conserved turn, a β-turn formed in the larger peptides. These analogs inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition. We outline the computational methods that were tried and used with the experimental information that led to the successful completion of this research.

The low-energy β− and electron emitter 161Tb as an alternative to 177Lu for targeted radionuclide therapy

The low-energy β− emitter 161Tb is very similar to 177Lu with respect to half-life, beta energy and chemical properties. However, 161Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to 177Lu. It also emits low-energy photons that are useful for gamma camera imaging. The 160Gd(n,γ)161Gd→161Tb production route was used to produce 161Tb by neutron irradiation of massive 160Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) 161Tb from the bulk of the 160Gd target and from its stable decay product 161Dy. 161Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. 177Lu. A 161Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera. Up to 15 GBq of 161Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%–90% of the available 161Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The 161Tb obtained was of the quality required to prepare 161Tb–DOTA-Tyr3-octreotate. We were able to produce 161Tb in n.c.a. form by irradiating highly enriched 160Gd targets; it can be obtained in the quantity and quality required for the preparation of 161Tb-labeled therapeutic agents.