The amphiphilic calixarene from the Guo group at Nankai University and amphiphilic cyclodextrin from the Ravoo group in Münster have been married for 4 years, and their coassemblies have made great progress in heteromultivalent recognition for complex biological systems.

In 2019, Nat. Chem. reported the heteromultivalent recognition of coassembly 1.0 (CD-CA) to tyrosine- and lysine-rich model peptides (Nat. Chem., 2019, 11, 86–93). The CD-CA had been successfully used to inhibit amyloid-β (Aβ) peptide fibrillation, dissolve mature fibrils, and reduce amyloid cytotoxicity. This work received widespread attention and lots of researchers asked whether we can futher explore the potential of coassembly for the treatment of Alzheimer’s disease (AD) in vivo. We are also very interested in that, because AD is the most prevalent type of dementia but only five drugs have been approved by Food and Drug Administration to treat AD over the past hundred years.

Revisiting the amino acid sequence of Aβ, we further constructed a novel coassembly using the guanidinium-modified amphiphilic calixarene (GCA) and amphiphilic cyclodextrin (CD). The new coassembly 2.0 (GCA-CD) exhibites extraordiniarily strong binding affinity ((3.29 ± 0.53) × 10¹³ M^-1) to Aβ₄₂ with exquisite specificity benefiting from the heteromultivalent recognition. As a result, GCA-CD is able to completely inhibit the fibrillation of Aβ₄₂ and disintegrate mature fibrils, moreover, effectively prevent the formation of oligomers and disintegrate oligomers. We then proved that GCA-CD can effectively mitigate the cell damage induced by Aβ₄₂ fibrils from aspects of cell viability, apoptosis, and oxidative stress. Thanks to the introduction of guanidinium groups, the GCA-CD can also promote the phagocytosis of Aβ₄₂ by microglia. In in vivo experiments, GCA-CD successfully reduced the contents of Aβ₄₂ plaques, soluble Aβ₄₂, insoluble Aβ₄₂, and Aβ₄₂ oligomers of 5xFAD mice. The behavioral experiments evidenced that GCA-CD can improve hippocampus-dependent learning ability and memory of 5xFAD mice. All these results collectively demostrate the prospects of GCA-CD as a novel anti-Aβ therapeutic agent for the treatment of AD. This work has been published in CCS Chemistry (DOI: 10.31635/ccschem.020.202000561).

Our exploration of the marriage of calixarene and cyclodextrin does not stop here, we believe the heteromultivalent recognition strategy is suitable for all complex biological systems, such as biomacromolecules and membranes. Therefore, this strategy exhibits versatile biomedical applications, including amyloidosis therapy, cell recognition, drug delivery, sensing array for complex systems to name just a few. These projects are ongoing in our lab.