Professor Ren Changliang and his collaborators have made important progress in the construction of artificial transmembrane channels and their anti-cancer applications

Recently, the team of Professor Ren Changliang, School of Pharmacy, State Key Laboratory of Cell Stress Biology, Fujian Provincial Key Laboratory of New Drug Target Research, and the team of Professor Zeng Huaqiang of the School of Chemistry of Fuzhou University reported the first cholesterol-promoting stable artificial nanopore
with transmembrane transport activity.
The ion transmembrane transport ability of the artificial nanopores is significantly positively correlated with the cholesterol content on the membrane, and the pore size and anticancer activity can be affected by adjusting the central side chain length of the pores, among which the nanopore Ch-C1 exhibits excellent anti-liver cancer activity and selectivity, which is expected Developed into a new type of anti-cancer drug
.
The relevant results are entitled "Cholesterol-stabilized membrane-active nanopores with anticancer activities".
Published online in Nature? Nature Communications magazine
.

Cholesterol is an important component of eukaryotic cell membrane structure, but is not normally present in bacterial cell membranes, and bacteria take advantage of this differentiation, Cholesterol-dependent cytolysin (CDC)
evolved.
CDC is a family of bacterial proteotoxins that assemble pore structures on the membrane only when cholesterol is present, thereby specifically targeting and harming eukaryotic cells, cleverly avoiding the damage
caused by toxins to bacteria themselves.
In addition, a subset of channel proteins exhibit similar activity to cholesterol upregulation, including: nicotinic acetylcholine receptors, epithelial sodium channels, transient receptor potential channels, and Alzheimer's β-amyloid peptide, etc
.
Examples of upregulating ion transmembrane transport activity by cholesterol, although numerous in nature, have not been explored
in the field of artificial transmembrane transport.

To answer these scientific questions, the team was inspired by the formation of a "barrel-plate" transmembrane channel with the assistance of ergosterol amphotericin B (AmB), and synthesized a series of rigid linear transmembrane molecules based on cholic acid derivatives.
It was also confirmed that the linear molecule can assemble into barrel-like nanopores
in the presence of cholesterol.
The transmembrane transport activity test showed that the transmembrane transport capacity of such pores was significantly regulated by the cholesterol content on the membrane, and the effect was optimal when the cholesterol was 50% of the phospholipid molecular content.
The pore size of the nanopores was determined by further planar lipid bilayer patch-clamp experiments, and it was found that the pore size decreased
with the lengthening of the central side chain.

Since the destruction of physiological balance inside and outside the cell membrane can easily lead to cell death, this work further explores the anti-cancer activity of this type of artificial nanopores: cell proliferation experiments have found that this kind of molecule has a good inhibition of hepatoma cell HepG2 Effects, of which Ch-C1 has the best activity, The_IC50 value is only 3.
8 μM
.
Surprisingly, Ch-C1 also shows excellent selectivity, with a high selectivity index for normal liver and kidney cells 12.
5 vs 130
.
Encouraged by the outstanding anti-liver cancer activity of Ch-C1, the team initially explored the anti-tumor mechanism of Ch-C1 and found it Ch-C1 can be permeable by disrupting cell membranes Thereby activating the Caspase-9 signaling pathway and inducing apoptosis
in hepatoma cells.
This important discovery provides a completely new way of thinking
about the development of novel anti-cancer drugs.

Xiamen University is the first signatory of the paper, and Professor Ren Changliang of the School of Pharmacy and Professor Zeng Huaqiang of Fuzhou University are the co-corresponding authors
of the paper.
This research was supported by the National Natural Science Foundation of China (22001221, 81971724 and U1903119), Shenzhen Science and Technology Innovation Commission (JCYJ20210324123411030).
, 2021Szuvp067) and Xiamen University President's Fund (20720210101
).
The research was also strongly supported by the team of Professor Wu Zhen, Associate Professor Wu Caisheng and Professor Wu Yunlong from the School of Pharmacy.

Links to papers: class="western" style="line-height:150%;margin-bottom:0in;">