Protein misfolding and aggregation have been associated with the pathogenesis of numerous serious and often highly debilitating diseases, chief among them neurodegenerative diseases such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), prion diseases (eg, “Mad Cow disease”), and type II diabetes, as well as at least 30 others. The amyloidoses that characterize many of these incurable diseases are self-assemblages of aberrantly aggregating proteins that form toxic oligomers and insoluble amyloid plaque. The challenges in inhibiting this aggregation are that, unlike traditional drug targets that have structurally defined and specifically active or specific binding sites, the toxic oligomers of amyloidogenic proteins are structurally metastable and capable of numerous conformations, and amyloid fibrils typically present flat surfaces.
To address these challenges, Gal Bitan, PhD, of the UCLA David Geffin School of Medicine, and a group of fellow researchers have developed a technique to specifically target the aberrantly self-associating proteins at the amino-acid interaction level. The “molecular tweezer,” CLR01, works through a process-specific mechanism that inhibits aggregation and toxicity of multiple amyloidogenic proteins, by competing for the same interactions that are key to the aggregation of most of these proteins.
CLR01 binds selectively to lysine, the only amino acid with a side-chain that effectively forms the 2 kinds of int
eractions important in facilitating aberrant protein self-assembly. In a zebrafish model of α-synuclein (α-syn) toxicity, CLR01 prevented deformation of α-syn by keeping it soluble, thus inhibiting neurotoxicity and promoting degradation of excess α-syn. In a triple-transgenic murine model of Alzheimer disease, peripheral subcutaneous CLR01 injection significantly decreased amyloid plaque burden and hyperphosphorylated tau, with an accompanying decrease in microgliosis.
Contributed by William Yarnall, RPh, CCP
Medical Writer, Connexion Healthcare