“Four-in-one” strategy for aspartic acid-assisted nanoscale spherical COFs controllable synthesis and biological application


Covalent organic frameworks (COFs) are organic crystalline polymers with well-defined molecular geometry and configurable porosity, as well as ultrahigh surface area, uniform sphere morphology, controllable particle size, and mesoporous microenvironment, which in fact allow them to efficiently load numerous therapeutic drugs and/or functional species. Amyloid‑β (Aβ) fibrils have been linked to a variety of neurological diseases, particularly Alzheimer’s disease (AD). Inhibition of Aβ aggregation has been proposed as a promising therapeutic strategy for preventing or treating AD. Despite significant number of clinical trials, small compounds or peptides as prospective inhibitors for AD therapy and prevention cannot yet meet the needs of successful clinical trials, possibly due to poor inhibitory efficiency, low blood brain barrier permeability, poor biocompatibility, and undesirable effects.

Due to the fact that methods to synthesize uniform COF spheres and to achieve optimal particle size while achieving water dispersibility and specific surface function are tedious and underdeveloped, researchers developed a simple strategy for simultaneous size control and surface functionalization of COF NSs via the Asp-assisted synthesis method. Asp performs four separate functions in the formation of COF NSs with the help of Asp: First reason being, the pKa of the carboxyl group of Asp is about 3.90, which is comparable to that of acetic acid (pKa = 4.74), so it is utilized as a catalyst for the creation of the imine bond based on the Schiff-base reaction instead of HAc; second reason is that the hydrophobic property of COF NSs will be eliminated by surface modification with Asp, which will increase their dispersion in aqueous solution and alleviate their application limitation; third reason is, Asp could act as a nucleation inhibitor and competitive modulator with multifunctional amine-based building components due to the dynamically reversible nature of the imine bond and the comparatively high reactive activity of alkyl amine; and the fourth reason is the chirality-selected chemical regulation of amyloid aggregation might be influenced by anchoring a chiral group onto the COF surface via the chiral block of D- and L-Asp.

In a new study published in ACS Applied Bio Materials, Hubei University scientists: Kai-Xiang Gao, Zhe Zhou, Linli Yao, Suxiao Wang, Yuexing Zhang, Qichao Zou, Li-Xin Ma, and led by Professor Hang-Xing Wang found out that D-Asp can increase dispersion in aqueous solutions and overcome poor water solubility of COF due to its hydrophobic nature. The research group successfully anchored D-Asp moiety onto the surface of COF spheres, which possess characteristics of uniform spheres, well dispersed, ultrahigh surface area, and good crystallinity and stability. The study demonstrated that D-Asp-COF possesses a larger binding affinity to Aβ compared with its enantiomer L-Asp-COF, D-Asp-COF improves inhibition efficiency and chiral discrimination to Aβ fibril aggregation.

According to the authors, the new study by Professor Hang-Xing Wang and colleagues reveals that Asp endows distinct features to the Asp-assisted synthetic method, including high-effective catalysis and construction of imine bond-based COF instead of Acetic acid (HAc), significantly improving the hydrophilic ability of COF NSs, precisely controlled growth of COF NSs following an end capping-confined growth mechanism, and artificial chiral interface-selected chemical modulation of Aβ fibrillation.

Given the urgent need to provide alternative therapies, natural products serve as vital resources for novel drugs. The observations by Hubei University scientists strongly suggest that the structural knowledge of the mechanism of action of these COF should be exploited as a starting point to design and develop therapeutic solutions for the prevention and treatment of AD.


Gao KX, Zhou Z, Yao L, Wang S, Zhang Y, Zou Q, Ma LX, Wang HX. Aspartic Acid-Assisted Size-Controllable Synthesis of Nanoscale Spherical Covalent Organic Frameworks with Chiral Interfaces for Inhibiting Amyloid-β Fibrillation. ACS Applied Bio Materials. 2022 Feb 22;5(3):1210-21.

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