Supramolecular Detoxification of Macromolecular Biotoxin through the Complexation by a Large‐Sized Macrocycle

Abstract

Biotoxins are diverse, complex, and hypertoxic, ultimately serving as grave and lasting menaces to humanity. Here, it is aimed to introduce a new detoxification methodology for macromolecular biotoxin through complexation by a very large macrocycle. A 25‐mer peptide isolated from Lycosa erythrognatha spider venom (LyeTxI) is selected as the model macromolecular biotoxin. Quaterphen[4]arene, with a side length of ≈1.6 nm, has a sufficient cavity to bind LyeTxI. Hence, the water‐soluble derivative of Quaterphen[4]arene (H) is designed and synthesized. H exhibits an overall host–guest complexation toward LyeTxI, resulting in a considerably high association constant of (7.01 ± 0.18) × 107 m−1. This encapsulation of peptide is interesting as traditional macrocycles can only engulf the amino acid residues of peptides due to their limited cavity size. In vitro assay verifies that complexation by H inhibits the interactions of LyeTxI with cell membranes, thereby reducing its cytotoxicity, suppressing hemolysis, and decreasing the release of lactate dehydrogenase. Notably, the intravenous administration of H has a significant therapeutic effect on LyeTxI‐poisoned mice, alleviating inflammation and tissue damage, and markedly improving the survival rate from 10% to 80%. An efficient and potentially versatile approach is provided to detoxify macromolecular biotoxins, with giant macrocycle serving as an antidote.

Synthesis of Cationic Biphen[4, 5]arenes as Biofilm Disruptors

“…Biphen[n]arenes (BPn), firstly reported by our group, [16] are a new family of macrocycles comprising biphenyl units linked by methylene bridges. The facile functionalization and excellent recognition properties enable their enormous potential in biomedical applications [17, 18] . On the other hand, previous studies have provided evidence for anti‐biofilm activity of cationic amphiphiles containing quaternary ammonium moieties [19] .…”

Recent advances in the synthesis and applications of macrocyclic arenes

“…Very recently, they introduced a new detoxification methodology for macromolecular biotoxin through complexation with a quaterphen [4]arene. 124 It could bind peptide Lycosa erythrognatha spider venom (LyeTxI) with a K a value in the magnitude of 10 7 M À1 . Moreover, the encapsulation of peptide Lycosa erythrognatha spider venom (LyeTxI) could reduce its cytotoxicity, suppress hemolysis, and decrease the release of lactate dehydrogenase.…”

Supramolecular detoxification of nitrogen mustardviahost–guest encapsulation by carboxylatopillar[5]arene

“…28 In general, these supramolecular antidotes could effectively encapsulate toxins, and thus decrease the concentration of active toxins below the efficacious dose and alleviate, and even eliminate, the toxicity accordingly. 27,30,41,53…”

“…27 Compared to previous strategies, the supramolecular strategy provides a target-to-target solution for poison treatment which greatly increases the targeting effect and decreases the side effects. [27][28][29][30] Biomedical applications based on supramolecular systems have been extensively developed over the past years, [31][32][33][34][35] which has led to major breakthroughs in the treatment of poisoning. 29,[36][37][38][39] Macrocyclic compounds, such as cyclodextrins, [40][41][42][43] calixarenes, [44][45][46][47] cucurbiturils, [48][49][50] and pillararenes, [51][52][53][54][55][56] display versatile host-guest properties toward bioactive compounds.…”

“…28 In general, these supramolecular antidotes could effectively encapsulate toxins, and thus decrease the concentration of active toxins below the efficacious dose and alleviate, and even eliminate, the toxicity accordingly. 27,30,41,53 The toxicity of nitrogen mustard is mainly due to the fact that nitrogen mustard readily undergoes rapid formation of toxic intermediate 2 in the aqueous phase. As NM is unstable in water, a potential antidote is expected to suppress the biological toxicity of intermediate 2, even deactivate the reactive intermediate, rather than NM itself.…”