Cyclic dipeptide‐based small molecules modulate zinc‐mediated liquid–liquid phase separation of tau

Abstract

Liquid–liquid phase separation (LLPS) is a complex physicochemical phenomenon mediated by multivalent transient weak interactions among macromolecules like polymers, proteins, and nucleic acids. It has implications in cellular physiology and disease conditions like cancer and neurodegenerative disorders. Many proteins associated with neurodegenerative disorders like RNA binding protein FUS (FUsed in Sarcoma), alpha‐synuclein (α‐Syn), TAR DNA binding protein 43 (TDP‐43), and tau are shown to undergo LLPS. Recently, the tau protein responsible for Alzheimer's disease (AD) and other tauopathies is shown to phase separate into condensates in vitro and in vivo. The diverse noncovalent interactions among the biomolecules dictate the complex LLPS phenomenon. There are limited chemical tools to modulate protein LLPS which has therapeutic potential for neurodegenerative disorders. We have rationally designed cyclic dipeptide (CDP)‐based small‐molecule modulators (SMMs) by integrating multiple chemical groups that offer diverse chemical interactions to modulate tau LLPS. Among them, compound 1c effectively inhibits and dissolves Zn‐mediated tau LLPS condensates. The SMM also inhibits tau condensate‐to‐fibril transition (tau aggregation through LLPS). This approach of designing SMMs of LLPS establishes a novel platform that has potential implication for the development of therapeutics for neurodegenerative disorders.

Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's disease

“…After completion of the reaction, as confirmed by TLC, formic acid was evaporated under reduced pressure, followed by co-evaporation with toluene (2 x 20 mL). The obtained residue was dried under a vacuum for 30 min and subjected to cyclization in sec-butanol (75 mL, 50 mM) under reflux conditions at 110 °C until the formation of a white precipitate was observed [ 9 , [29] , [35] ].…”

“…Increased Fe 3+ levels contribute to tau aggregation through hyperphosphorylation and by facilitating LLPS of tau, leading to NFTs [ 7 , 8 ]. Small molecules, natural products, and polymer-based inhibitors have shown potential in modulating tau fibrillization, while targeting Fe 3+ -induced LLPS of tau is an emerging approach [ [9] , [10] , [11] ].…”

“…Furthermore, their potential as brain shuttles for drug delivery is of significant interest [ 30 , 31 ]. The enhanced structural rigidity, molecular recognition and biocompatibility of CDPs make them attractive pharmacophores [ 9 , 32 , 33 ]. We rationally designed and synthesized hybrid molecules by strategically integrating the structural and functional features of GA and CDPs to enhance their multifunctional therapeutic properties [ 34 ].…”

Biphasic modulation of tau liquid–liquid phase separation by polyphenols

“…27 We have developed a cyclic dipeptide derivative that effectively inhibits and dissolves Zn-mediated tau condensates preventing the tau condensate-to-fibril transition. 28 MB was shown to promote tau LLPS and accelerate the gel transition from matured tau droplets, thereby reducing the fibrillation and cytotoxicity. 29 The complex role of LLPS in driving the fibrillation process necessitates the need for identifying molecular modulators of tau LLPS.…”

Chemical control of phase separation in DNA solutions

“…5 Because nucleic acid interactions based on Watson–Crick base pairing are relatively straightforward, it provides an opportunity to design nucleic acid sequences with programmable LLPS properties. Control of LLPS was previously shown using temperature, 12,13 enzymatic pH-modulation, 14 light, 15 small molecules, 16,17 and size-specific diffusion of ATP through pores in lipid bilayers. 18…”