Lifespan.io reports that researchers have reduced memory and learning symptoms in mice. Alzheimer’s research needs new approaches. A paper describes a promising molecule built using a technique that can be expanded to numerous other proteins with post-translational modifications. The researchers were also able to deliver the rather large molecule intranasally across the blood-brain barrier, alleviating symptoms of Alzheimer’s. However, murine models of Alzheimer’s are not completely adequate.
Recent progress in the field of targeted protein degradation (TPD) has proven its immense potential as a novel therapeutic modality in drug discovery. In 2015, Bradner and his colleagues devised a phthalimide-based small molecule that promotes degradation of transcriptional coactivator BRD4 by hijacking the Cereblon (CRBN) E3 ubiquitin ligase complex.
In the same year, Crews and his colleagues also reported a TPD technology recruiting the von Hippel–Lindau (VHL) E3 ligase complex, commonly referred to as proteolysis-targeting chimeras (PROTACs).
These technologies feature bifunctional small molecules that bring the proteins of interest into proximity with the E3 ubiquitin ligase complexes for ubiquitination and subsequent proteasomal degradation.
Such TPD-based small molecules have several advantages over traditional small molecule inhibitors in that they eliminate the target protein instead of modulating its function.
TPD technology thus can complement nucleic acid-based gene knockdown in removing unwanted intracellular proteins. In addition, the TPD technique can target a plethora of proteins in various compartments of the cell, including disease-causing proteins that have previously been considered undruggable with the conventional small-molecule approach. Recently, several strategies have been suggested to potentiate therapeutic efficacy of TPD technology.
In particular, TPD molecules that recognize and bind to the protein with specific post-translational modifications (PTMs), such as phosphorylation, may be a novel strategy to induce selective degradation of pathological proteins attributed to aberrant PTMs.
However, a TPD molecule specifically targeting post-translationally modified proteins has not been reported yet.
Brian Wang is a Futurist Thought Leader and a popular Science blogger with 1 million readers per month. His blog Nextbigfuture.com is ranked #1 Science News Blog. It covers many disruptive technology and trends including Space, Robotics, Artificial Intelligence, Medicine, Anti-aging Biotechnology, and Nanotechnology.
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