Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

Abstract

Molecular tweezers represent the first class of artificial receptor molecules that made the way from a supramolecular host to a drug candidate with promising results in animal tests. Due to their unique structure, only lysine and arginine are well complexed with exquisite selectivity by a threading mechanism, which unites electrostatic, hydrophobic and dispersive attraction. However, tweezer design must avoid self-dimerization, self-inclusion and external guest binding. Moderate affinities of the molecular tweezers towards sterically well accessible basic amino acids with fast on and off rates protect normal proteins from a potential interference with their biological function. However, the early stages of abnormal Aβ, α-synuclein, and TTR assembly are redirected upon tweezer binding towards the generation of amorphous non-toxic material that can be degraded by the intracellular and extracellular clearance mechanisms. Thus, specific host–guest chemistry between aggregation-prone proteins and lysine/arginine binders rescues cell viability and restores animal health in models of AD, PD, and TTR amyloidosis.

Native Top-Down Mass Spectrometry and Ion Mobility Spectrometry of the Interaction of Tau Protein with a Molecular Tweezer Assembly Modulator

“…It acts as a unique nanochaperone, which rather than assisting in the folding of the native structure, prevents formation of toxic oligomers and aggregates. A derivative compound, CLR03, that shares the polar bridgehead structure but lacks the hydrophobic arms, was designed as a negative control [25]. The mechanism of MT inhibition is based on competing electrostatic and hydrophobic interactions, which are essential for abnormal self-assembly and aggregation.…”

Inhibition of Mutant αB Crystallin‐Induced Protein Aggregation by a Molecular Tweezer

“…The molecular tweezer CLR01 is a broad‐spectrum nanochaperone that inhibits abnormal protein self‐assembly by binding selectively to lysine residues, preventing aggregation and decreasing the toxicity of multiple amyloidogenic proteins . Selective binding to lysine is achieved by a combination of hydrophobic and electrostatic interactions, which are important in aberrant protein self‐assembly .…”

Using Molecular Tweezers to Remodel Abnormal Protein Self-Assembly and Inhibit the Toxicity of Amyloidogenic Proteins

“…The species, specific disease models, and route of administration vary according to the goals of the experiment. To date, most experiments have tested CLR01 in mice or fish [13]. Below are examples of protocols suitable for measuring BBB penetration of CLR01 in mice by spiking the compound with a radiolabeled derivative, and for treating mice by s.c. administration via osmotic minipumps.…”

“…The current lead MT derivative, CLR01 (Fig. 1), has been used successfully to inhibit abnormal protein aggregation and dissociate pre-formed aggregates in vitro, protect cultured cells from the toxicity of various amyloidogenic proteins, and provide therapeutic effects in multiple animal models [12,13]. Importantly, CLR01 has been shown to have a high safety margin [14], supporting the use of MTs as attractive therapeutic drug candidates for proteinopathies.…”