Hang Yin

Xiangjun Zhang

Jianwen Wei

Siyu Lu

David Bardelang
email: david.bardelang@univ-amu.fr

Ruibing Wang
email: rwang@um.edu.mo

Recent advances in supramolecular antidotes

Keywords: Poisons, Macrocycles, Supramolecular Chemistry, Antidotes, Host-guest

Poisons always have fascinated humankind. Initially considered as deleterious or hazardous substances, modern era has witnessed the controlled utilization of dangerous poisons in medicine and in cosmetics.

Simultaneously, antidotes have become crucial as reversal agents to counteract the effects of a poison, and they are also used today to positively cancel the benefits of a poison after use. Currently, the majority of poisons is composed of small molecules. This review focuses on recent developments to reverse or prevent toxic effects of poisons by encapsulation in host molecules. Cyclodextrins, cucurbiturils, acyclic cucurbituril derivatives, calixarenes, and pillararenes, have been reported to largely impact the effects of toxic compounds, thus extending the current paradigm of small molecule antidotes by adding a new family of macrocyclic compounds to the current arsenal of antidotes.

Introduction

The utilization of poisons (compounds causing harm, injury or death) seems to have preceded the invention of Writing (beginning of History) by at least 500 years [START_REF] Nepovimova | The history of poisoning: from ancient times until modern ERA[END_REF]. With various applications including probable uses for hunting and social recognition/promotion within early human groups, poisons have then mostly been used for suicide, pest-control, and assassination since Antiquity and generally up to the Renaissance period. According to the World Health Organization, unintentional poisoning remains a problem for modern society, with several million people affected each year [START_REF]The public health impact of chemicals: knowns and unknowns[END_REF]. Yet, new forms of poisons have started to be widely applied for example as pesticides, key intermediates in the chemical industry, disinfectants, conservatives, or in medicine for instance in surgery (i. e. curare alkaloids [START_REF] Raghavendra | Neuromuscular Blocking Drugs: Discovery and Development[END_REF], previously discovered and used by Amazonian Indians, Figure 1A) or in cosmetics (botulinum toxin [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF], a neurotoxic protein that is also the most toxic substance known, Figure 1A). Excluding physical instances, poisons can be chemicals (ions or small molecules) or biological (peptides or proteins such as those found in animals' venoms).

In parallel, many antidotes (substances able to counter the effects of a poison or a disease) have been discovered

with time (such as mithridate, an ancient antidote with complex formulation) and most lethal poisons today have antidotes such as cyanide (antidote sodium nitrite or thiosulfate), opioids (antidote naloxone), lead (antidote the succimer chelator), heparin (antidote protamine sulfate) or the three medications methotrexate, trimethoprim and pyrimethamine sharing the same antidote: leucovorin. Modern approaches include the production of specific antibodies to counter the effects of venoms [START_REF] Parreño | A synthetic biology approach for consistent production of plant-made recombinant polyclonal antibodies against snake venom toxins[END_REF]. However, several poisons still do not have antidotes, such as the alkaloids aconitine (from acotinum plant sometimes used in medicine), or coniine, N-methylconiine and conhydrine (from hemlock plant), famous as the basis for the beverage forced to swallow and having caused death of the Greek philosopher Socrates (399 BC). The glycoprotein ricin, besides its mention in several fictions, is one of the most toxic substances [START_REF] Audi | Ricin PoisoningA Comprehensive Review[END_REF] for which there is no known antidote and that has seriously been considered as a warfare agent. As mentioned above, besides antibodies used as antidotes against venoms, most antidotes are small molecules.

In the past 30 years, the Nobel Prize in Chemistry has been awarded twice to researchers focused on supramolecular systems, more specifically for their contributions toward "the development and use of molecules with structure-specific interactions of high selectivity" (1987) and for "the design and synthesis of molecular machines" (2016) [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF]. For both research fields, macrocyclic compounds were central in the findings that have led to major breakthroughs. Yet, despite these significant advances, practical applications stemming from supramolecular chemistry remain relatively limited [8][START_REF] Rios | Synthetic Receptors for the High-Affinity Recognition of O-GlcNAc Derivatives[END_REF][START_REF] Deyle | Phage Selection of Cyclic Peptides for Application in Research and Drug Development[END_REF][START_REF] Tromans | A biomimetic receptor for glucose[END_REF][START_REF] Mateus | Allosteric Recognition of Homomeric and Heteromeric Pairs of Monosaccharides by a Foldamer Capsule[END_REF]. As perhaps one of the most famous family of macrocycles, cyclodextrins (artificial host molecules of natural origin) have started to be used in the pharmaceutical and cosmetic industries (Figure 2) [START_REF] Davis | Cyclodextrin-based pharmaceutics: past, present and future[END_REF][START_REF] Crini | Fundamentals and Applications of Cyclodextrins[END_REF]. In the meantime, supramolecular chemists have developed numerous other host molecules with various topologies, including some resembling crowns (crown ethers), cups (calix[n]arenes), pumpkins (cucurbit[n]urils), clips (acyclic cucurbit[n]uril congeners), or tubes (pillar[n]arenes, see Figure 2), n denoting the number of monomer repeat units, among others [START_REF] Liu | Surveying macrocyclic chemistry: from flexible crown ethers to rigid cyclophanes[END_REF].

Drug delivery systems are one of the most attractive research areas in pharmaceutical science [START_REF] Peer | Nanocarriers as an emerging platform for cancer therapy[END_REF][START_REF] Björnmalm | Bridging Bio-Nano Science and Cancer Nanomedicine[END_REF][START_REF] Zhou | Supramolecular chemotherapy based on host-guest molecular recognition: a novel strategy in the battle against cancer with a bright future[END_REF], and even if a variety of nano systems have shown great efficacy [START_REF] Peer | Nanocarriers as an emerging platform for cancer therapy[END_REF][START_REF] Björnmalm | Bridging Bio-Nano Science and Cancer Nanomedicine[END_REF], surprising advances have been achieved at the molecular level [START_REF] Zhou | Supramolecular chemotherapy based on host-guest molecular recognition: a novel strategy in the battle against cancer with a bright future[END_REF]. Scientists have discovered that simple host-guest complexes can also make good drug delivery systems, with marked advantages for some of them to alleviate or reverse side-effects or toxicities of drugs both in vitro and in vivo when these drugs are encapsulated by host molecules [START_REF] Zhou | Supramolecular chemotherapy based on host-guest molecular recognition: a novel strategy in the battle against cancer with a bright future[END_REF][START_REF] Wang | Highly Effective Binding of Viologens by p-Sulfonatocalixarenes for the Treatment of Viologen Poisoning[END_REF][START_REF] Yin | Applications of Cucurbit[n]urils (n=7 or 8) in Pharmaceutical Sciences and Complexation of Biomolecules[END_REF]. Indeed, the toxicity or unforeseen side-effects of biologically active molecules can limit their clinical applicability or cause the interruption of a drug development program. With the rapid growth of the number of reported host molecules [START_REF] Yu | Reactions of Folded Molecules in Water[END_REF][START_REF] Sullivan | The thermodynamics of guest complexation to octa-acid and tetra-endo-methyl octa-acid: reference data for the sixth statistical assessment of modeling of proteins and ligands (SAMPL6)[END_REF][START_REF] Yang | Naphthotubes: Macrocyclic Hosts with a Biomimetic Cavity Feature[END_REF], many macrocycles have shown interesting binding properties toward bioactive compounds, and some of them, good inhibition/reversal effects against toxic compounds and drugs exhibiting adverse sideeffects [START_REF] Wang | Highly Effective Binding of Viologens by p-Sulfonatocalixarenes for the Treatment of Viologen Poisoning[END_REF][START_REF] Yin | Applications of Cucurbit[n]urils (n=7 or 8) in Pharmaceutical Sciences and Complexation of Biomolecules[END_REF][START_REF] Ma | Acyclic Cucurbit[n]uril-Type Molecular Containers Bind Neuromuscular Blocking Agents In Vitro and Reverse Neuromuscular Block In Vivo[END_REF]. Different from the complex supramolecular systems that may involve different types of interactions [START_REF] Wang | Peptide self-assembly: thermodynamics and kinetics[END_REF][START_REF] Yuan | Hierarchically oriented organization in supramolecular peptide crystals[END_REF], the host-guest interaction is mainly attributed to one of the various interactions, such as hydrogen bond, electrostatic interaction, and hydrophilic/hydrophobic interactions, etc. Especially, the electrostatic interaction driven host-guest complex generally demonstrate high binding affinities [START_REF] Barrow | Cucurbituril-Based Molecular Recognition[END_REF]. However, the potential of host molecules as antidotes has never been summarized. In this context, host molecules having showed inhibition or reversal of biological properties for a given compound are the object of the present review with highlights on the most promising host molecules used as antidotes, and on products that are now on the market.

Cyclodextrins

Cyclodextrins (CDs, Figure 2B) are considered as one of the oldest known families of host molecules, and their discovery over a century ago predates the establishment of supramolecular chemistry as a scientific discipline.

CDs are sugar-based cyclic oligomers made from the bacterial degradation of starch and have a versatile hydrophobic cavity amenable for binding a plethora of guest molecules [START_REF] Szejtli | Introduction and General Overview of Cyclodextrin Chemistry[END_REF].

Reversal of neuromuscular blocking agents

Even if CDs are usually considered as non-toxic, they did not attract much attention as antidote until Zhang and co-workers used a γ-CD derivative (sugammadex, Figure 2B) to reverse the effects of neuromuscular blocking agents (NMBAs) in 2002 (Figure 3) [START_REF] Bom | A Novel Concept of Reversing Neuromuscular Block: Chemical Encapsulation of Rocuronium Bromide by a Cyclodextrin-Based Synthetic Host[END_REF][START_REF] Adam | Cyclodextrin-Derived Host Molecules as Reversal Agents for the Neuromuscular Blocker Rocuronium Bromide: Synthesis and Structure-Activity Relationships[END_REF].

NMBAs are mono-and most often di-quaternary ammonium compounds derived from curare or malouetine (like rocuronium or cisatracurium, Figure 1), binding post-synaptic acetylcholine receptors and causing paralysis of skeletal muscles [START_REF] Hunter | New Neuromuscular Blocking Drugs[END_REF]. They are often used to complement anesthesia. With a high binding affinity Ka of (1.05±0.16)×10 7 M -1 between sugammadex and rocuronium, the host compound could efficiently reverse the rocuronium-induced neuromuscular blocking effect in vivo, that has paved the way to the development of supramolecular antidotes [START_REF] Bom | A Novel Concept of Reversing Neuromuscular Block: Chemical Encapsulation of Rocuronium Bromide by a Cyclodextrin-Based Synthetic Host[END_REF]. The success of this approach was soon followed by subsequent studies, further establishing sugammadex as an effective antidote [START_REF] Naguib | Sugammadex: Another Milestone in Clinical Neuromuscular Pharmacology[END_REF]. Finally, sugammadex has been commercialized by Merck with the trade name of Bridion®. Despite this success, sugammadex is not without shortcomings. Its approval by the U.S. Food and Drug Administration (FDA) has been delayed due to its association with anaphylaxis [START_REF] Tsur | Hypersensitivity associated with sugammadex administration: a systematic review[END_REF].

In addition, sugammadex-induced bradycardia and asystole cannot be ignored [START_REF] Hunter | Sugammadex-induced bradycardia and asystole: how great is the risk?[END_REF]. These side-effects could be due to unspecific binding and hence, new host molecules with better affinities would be interesting to test.

Clearance of bile acids

Liu and co-workers studied the binding of bile acids (BAs) such as cholic acid (CA), deoxycholic acid (DCA), glycocholic acid (GCA), and taurocholic acid (TCA, Figure 1B), with L/D-tyrosine-modified β-CDs (L/D-Tyr-β-CDs) or L/D-tryptophan-modified β-CDs (L/D-Trp-β-CDs, Figure 2B) and strong affinities were observed in most cases [START_REF] Chen | Thermodynamic Origin of Selective Binding of β-Cyclodextrin Derivatives with Chiral Chromophoric Substituents toward Steroids[END_REF]. However, Liu et al. postulated that the -COOH groups on both host and guest molecules could have hindered an efficient recognition between these β-CD derivatives and BAs due to electrostatic repulsions between carboxylate groups. They thus synthesized a tyramine-modified β-CD (Trm-β-CD) to verify their assumption [START_REF] Zhang | Reversing the Cytotoxicity of Bile Acids by Supramolecular Encapsulation[END_REF]. In general, this new host has showed stronger affinities than L/D-Tyr-β-CDs and L/D-Trp-β-CDs toward BAs. Both in vitro (HT-29 and HCT-116 cell lines) and in vivo (mice) studies showed that Trm-β-CD can reverse the cytotoxicity of DCA and accelerate the clearance of blood DCA, suggesting a promising future for this host with respect to intrahepatic cholestasis and other BA-related diseases.

Calixarenes

Calix[n]arenes (C[n]As) were named like this on account of their shape, resembling that of a chalice or grail (Figure 2B) [37]. These host molecules have been studied for decades and many accomplishments have been achieved in various research areas [START_REF] Liu | Surveying macrocyclic chemistry: from flexible crown ethers to rigid cyclophanes[END_REF]. However, the poor water solubility and relatively high toxicity of these compounds have limited their application in biomedical sciences [START_REF] Guo | Supramolecular Chemistry of p-Sulfonatocalix[n]arenes and Its Biological Applications[END_REF]. Despite these drawbacks, scientists have developed several methods to facilitate the use of C[n]As in the biomedical field. The most promising strategy turned to be the synthesis of water soluble and less toxic C[n]A derivatives: p-sulfonatocalix[n]arenes (SC[n]As, n = 4-8, Figure 2B) [START_REF] Guo | Supramolecular Chemistry of p-Sulfonatocalix[n]arenes and Its Biological Applications[END_REF].

Antidote for pesticide poisoning

Liu and co-authors have studied the recognition of the pesticide paraquat (PQ, Figure 1B) by SC[n]A (n = 4, 5) in several phosphate buffers (pH = 2.0, 7.2, and 12.0) [START_REF] Guo | Highly Effective Binding of Methyl Viologen Dication and Its Radical Cation by p-Sulfonatocalix[4,5]arenes[END_REF]. PQ forms a stable complex with SC [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF]A (binding constant Ka ≈ 10 4 M -1 at all pH), while the corresponding value for the PQ•SC [START_REF] Parreño | A synthetic biology approach for consistent production of plant-made recombinant polyclonal antibodies against snake venom toxins[END_REF]A complex (Ka ≈ 10 3 M -1 ) raised to 10 5 M -1 when the pH was increased from 2.0 to 12.0 [START_REF] Guo | Highly Effective Binding of Methyl Viologen Dication and Its Radical Cation by p-Sulfonatocalix[4,5]arenes[END_REF]. Later, the potential of SC [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF]A, SC [START_REF] Parreño | A synthetic biology approach for consistent production of plant-made recombinant polyclonal antibodies against snake venom toxins[END_REF]A, and a newly introduced p-sulfonatothiacalix [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF]arene (STC[4]A) was studied as host compounds for the treatment of viologens poisoning using paraquat and diquat as poisons [START_REF] Wang | Highly Effective Binding of Viologens by p-Sulfonatocalixarenes for the Treatment of Viologen Poisoning[END_REF]. Upon encapsulation, the transformation of oxygen to superoxide (O2 •-) was reduced, thereby inhibiting the generation of hydroxyl radicals (HO • ), and decreasing the toxicity of viologens. Subsequently, the PQ•SC [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF]A complex was selected for an in vivo pharmacokinetic study involving oral administration [START_REF] Wang | Paraquat Detoxification with p-Sulfonatocalix-[4]arene by a Pharmacokinetic Study[END_REF]. Compared to the group of rats treated with PQ alone, the group treated with PQ•SC [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF]A showed lower PQ concentrations in plasma (Figure 4). These results were supported and tentatively explained by an in vitro intestinal absorption study, that showed an inhibition of PQ absorption by the intestines, when SC [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF]A was present [START_REF] Wang | Paraquat Detoxification with p-Sulfonatocalix-[4]arene by a Pharmacokinetic Study[END_REF]. SC[n]A macrocycles are further chemically tunable and could thus be another family of supramolecular antidotes in the near future.

Antidote of heparin

Unfractionated heparin (UFH) is widely used in clinical practice as an anticoagulant agent. However, when overdosed or administered in sensitive populations, UFH may cause several side effects Including excessive bleeding [START_REF] Huang | Heparin reversal by an oligoethylene glycol functionalized guanidinocalixarene[END_REF]. The only clinically available UFH neutralization agent, protamine, has several risks as well associated with its use, Including allergic reactions in a large sub-population of patients [START_REF] Huang | Heparin reversal by an oligoethylene glycol functionalized guanidinocalixarene[END_REF]. Hence, it is essential to develop novel UFH neutralizers to reverse heparinization in an effective and safe manner, as a replacement or supplementary of protamine. Very recently, a biocompatible oligoethylene glycol functionalized guanidinocalixarene (GC [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF]AOEG), which binds with UFH with high binding affinity (10 7 M -1 ), was designed as a supramolecular antidote against UFH. In vivo tests in three mouse bleeding models showed that GC [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF]AOEG can effectively alleviate excessive bleeding induced by UFH with an excellent safety profile, indicating a great potential of GC [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF]AOEG for clinical translation as a UFH neutralizer [START_REF] Huang | Heparin reversal by an oligoethylene glycol functionalized guanidinocalixarene[END_REF].

Cucurbiturils

Cucurbit [START_REF] Audi | Ricin PoisoningA Comprehensive Review[END_REF]uril had received only modest attention until the groups of Kim and Day successfully isolated several homologues (cucurbit[n]urils: CB[n]s, n = 5-8, Figure 2B) forming in 2000 a new family of host molecules and opening new avenues for macrocyclic chemistry [START_REF] Barrow | Cucurbituril-Based Molecular Recognition[END_REF][START_REF] Kim | New Cucurbituril Homologues: Syntheses, Isolation, Characterization, and X-ray Crystal Structures of Cucurbit[n]uril (n = 5, 7, and 8)[END_REF][START_REF] Day | Method for synthesis cucurbiturils[END_REF][START_REF] Lee | Cucurbituril Homologues and Derivatives: New Opportunities in Supramolecular Chemistry[END_REF][START_REF] Lagona | The Cucurbit[n]uril Family[END_REF][START_REF] Masson | Cucurbituril chemistry: a tale of supramolecular success[END_REF][START_REF] Assaf | Cucurbiturils: from synthesis to high-affinity binding and catalysis[END_REF][START_REF] Cheng | A pH-driven ring translocation switch against cancer cells[END_REF][START_REF] Gao | A user-friendly herbicide derived from photo-responsive supramolecular vesicles[END_REF][START_REF] Combes | Triangular Regulation of Cucurbit[8]uril 1:1 Complexes[END_REF][START_REF] Yin | A Cucurbit[8]uril 2:2 Complex with a Negative pKa Shift[END_REF]. Like CDs, these synthetic macrocycles are usually considered as relatively non-toxic compounds [START_REF] Chen | Developmental and organ-specific toxicity of cucurbit[7]uril: in vivo study on zebrafish models[END_REF][START_REF] Zhang | A systematic evaluation of the biocompatibility of cucurbit[7]uril in mice[END_REF][START_REF] Uzunova | Toxicity of cucurbit[7]uril and cucurbit[8]uril: an exploratory in vitro and in vivo study[END_REF][START_REF] Hettiarachchi | Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers[END_REF]. In 2004 [START_REF] Wheate | Multi-nuclear platinum complexes encapsulated in cucurbit[n]uril as an approach to reduce toxicity in cancer treatment[END_REF] and 2005 [START_REF] Jeon | Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug[END_REF], two seminal papers have reported the encapsulation of platinum drugs in CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] in an approach to reduce their toxicity. In 2011, Gilson and co-authors found that CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] could tightly bind amantadine (AD, Figure 1B, an antiviral medication also used against Parkinson's disease; Ka = 1.7±0.8×10 14 M -1 ) [START_REF] Moghaddam | New Ultrahigh Affinity Host-Guest Complexes of Cucurbit[7]uril with Bicyclo[2.2.2]octane and Adamantane Guests: Thermodynamic Analysis and Evaluation of M2 Affinity Calculations[END_REF]. This discovery demonstrated that CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] could be employed as a latent competitor against natural receptors for the binding of small molecules. In parallel, the Wang's group has systemically studied a series of cases for which CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] was used as a potential antidote or toxicity-inhibitory agent. In particular, CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] was found to have a significant potential as a neural toxicity reversal agent [START_REF] Chen | In vivo reversal of general anesthesia by cucurbit[7]uril with zebrafish models[END_REF][START_REF] Li | Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor[END_REF][START_REF] Huang | Inhibition of drug-induced seizure development in both zebrafish and mouse models by a synthetic nanoreceptor[END_REF].

Alleviation of neurotoxicity

CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] was found to accelerate the recovery of zebrafish that had been anaesthetized by tricaine mesylate (TM, Figure 1B), an FDA-approved general anesthetic [START_REF] Chen | In vivo reversal of general anesthesia by cucurbit[7]uril with zebrafish models[END_REF]. In addition, CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] was found to inhibit the neurotoxicities of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, Figure 1B), a neurotoxin that is used to construct Parkinson's disease models, and its active metabolite N-methyl-4-phenylpyridine (MPP + ) in a study relying on zebrafish [START_REF] Li | Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor[END_REF]. CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] was then shown to reduce the toxicity of pentylenetetrazol (PTZ, Figure 1B), a neurotoxin inducing seizure, on zebrafish and mice (Figure 5) [START_REF] Huang | Inhibition of drug-induced seizure development in both zebrafish and mouse models by a synthetic nanoreceptor[END_REF].

Results obtained with these models are presumably due to the relatively strong binding affinities between CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] and the neurotoxic compounds. Indeed, CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] forms 1:1 host-guest complexes with TM, MPTP, MPP + , and PTZ, with relatively high binding constants of the order of ~10 5 M -1 , starting to make CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] a good competitor impeding the binding between neurotoxins and their natural receptors [START_REF] Chen | In vivo reversal of general anesthesia by cucurbit[7]uril with zebrafish models[END_REF][START_REF] Li | Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor[END_REF][START_REF] Huang | Inhibition of drug-induced seizure development in both zebrafish and mouse models by a synthetic nanoreceptor[END_REF]. Following the reversal of neurotoxicities by CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF], the ability for this macrocycle to reverse or inhibit other toxicities has been evaluated.

Alleviation of cardiotoxicity

Cardiotoxicity is one of the high-risk side effects of bioactive compounds, often inducing cardiac dysfunctions.

In this context, CB[n]s pleasingly showed good efficacy in alleviating cardiotoxicities of several bioactive molecules [START_REF] Li | Complexation of clofazimine by macrocyclic cucurbit[7]uril reduced its cardiotoxicity without affecting the antimycobacterial efficacy[END_REF][START_REF] Kuok | Supramolecular strategy for reducing the cardiotoxicity of bedaquiline without compromising its antimycobacterial efficacy[END_REF][START_REF] Yang | Supramolecular alleviation of cardiotoxicity of a small-molecule kinase inhibitor[END_REF][START_REF] Yin | Supramolecular Encapsulation and Bioactivity Modulation of a Halonium Ion by Cucurbit[n]uril (n = 7, 8)[END_REF]. For instance, clofazimine (CFZ, Figure 1B) is a drug that was developed for the treatment of tuberculosis but suffers from cardiotoxicity and a poor solubility in water [START_REF] Li | Complexation of clofazimine by macrocyclic cucurbit[7]uril reduced its cardiotoxicity without affecting the antimycobacterial efficacy[END_REF]. After encapsulation in CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] (Ka ≈ 10 4 ~10 5 M -1 ), the water solubility of CFZ increased in both acidic and neutral media, and in vitro and in vivo tests have shown drops of CFZ cardiotoxicity without affecting its antimycobacterial activity [START_REF] Li | Complexation of clofazimine by macrocyclic cucurbit[7]uril reduced its cardiotoxicity without affecting the antimycobacterial efficacy[END_REF]. Bedaquiline (BDQ, Figure 1B), another anti-tuberculosis drug, is also prone to the same issues. The solubility of BDQ increased with CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] by a factor of 0.27-fold of the concentration of CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF]. Meanwhile, in vivo tests including a set of physiological parameters for cardiac functions showed that the cardiotoxicity of BDQ was dramatically decreased in the presence of CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] [START_REF] Kuok | Supramolecular strategy for reducing the cardiotoxicity of bedaquiline without compromising its antimycobacterial efficacy[END_REF]. Sorafenib (SO, Figure 1B) is a small-molecule kinase inhibitor (SMKI) that is widely used in the treatment of various cancers [START_REF] Yang | Supramolecular alleviation of cardiotoxicity of a small-molecule kinase inhibitor[END_REF], but is also characterized by a significant cardiotoxicity. Relatively high affinity between SO and CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] (Ka = (2.87 ± 0.13)×10 5 M -1 ) enabled this host to decrease SO cardiotoxicity without affecting the desired activity, as confirmed in vitro (with SMMC7721 cell lines) and in vivo (with zebrafish models) [START_REF] Yang | Supramolecular alleviation of cardiotoxicity of a small-molecule kinase inhibitor[END_REF]. Diphenyleneiodonium (DPI, Figure 1B) is an uncompetitive inhibitor of flavoenzymes able to reduce the activity of NADPH oxidase, xanthine oxidase, and nitric oxide synthase [START_REF] Yin | Supramolecular Encapsulation and Bioactivity Modulation of a Halonium Ion by Cucurbit[n]uril (n = 7, 8)[END_REF]. However, a latent cardiotoxicity of DPI presents risks when used in vivo. Both CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] and CB [8] form stable complexes with DPI in aqueous solution, CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] being singly complexed and CB [8] doubly bound (Ka DPI•CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] = (3.13±0.16)×10 4 M -1 , and Ka DPI•CB [8] = 2.26×10 12 M -2 ), but CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] showed better performance in reducing the cardiotoxicity of DPI, likely due to its better solubility compared to that of CB [8] [START_REF] Yin | Supramolecular Encapsulation and Bioactivity Modulation of a Halonium Ion by Cucurbit[n]uril (n = 7, 8)[END_REF].

Alleviation of hepatotoxicity

Natural products are an important source of new medicines, but their hepatotoxicities can present serious concerns. For instance, arecoline (AH, Figure 1B) is an active compound extracted from Areca nut that has been studied for the treatment of several neurological disorders, but also relatively to the cardiovascular and digestive systems. However, AH can show severe hepatotoxic effects [START_REF] Li | Alleviation of Hepatotoxicity of Arecoline (Areca Alkaloid) by a Synthetic Receptor[END_REF] so CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] was tested as a supramolecular antidote to minimize its hepatotoxicity. The association between AH and CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] was first studied and has shown formation of a 1:1 complex with a binding affinity Ka of (1.21±0.12)×10 3 M -1 . Subsequent work demonstrated a reduction of the hepatic toxicity of AH in vitro based on tests performed on L02 cell lines [START_REF] Li | Alleviation of Hepatotoxicity of Arecoline (Areca Alkaloid) by a Synthetic Receptor[END_REF].

Nitidine chloride (NC, Figure 1B) is a natural alkaloid extracted from the root of Zanthoxylum nitidum [START_REF] Li | Supramolecular formulation of nitidine chloride can alleviate its hepatotoxicity and improve its anticancer activity[END_REF] and a promising drug candidate against cancer, but further studies were impeded by its hepatic toxicity. A novel formulation of NC with CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] was tested, enabling to boost its anti-cancer activity (IC50 = 2.94±0.15 μM compared to 7.28±0.36 μM for free NC) [START_REF] Li | Supramolecular formulation of nitidine chloride can alleviate its hepatotoxicity and improve its anticancer activity[END_REF] while reducing its hepatotoxicity (IC50 = 3.48±0.49 μM), by a factor of ~2 (IC50 = 6.87±0.80 μM for free NC) in vitro. Trazodone (TZ, Figure 1B) is an FDA-approved drug that has been developed for the treatment of depression. However, its active metabolite, m-chlorophenylpiperazine (mCPP), has been associated with hepatotoxicity. An in vitro study showed that CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] could complex these two compounds and significantly decrease the hepatotoxicities caused by TZ and mCPP [START_REF] Huang | Alleviating the hepatotoxicity of trazodone via supramolecular encapsulation[END_REF]. These results were confirmed in vivo highlighting the potential of this formulation for clinical applications [START_REF] Huang | Alleviating the hepatotoxicity of trazodone via supramolecular encapsulation[END_REF].

Alleviation of general cytotoxicity

The administration of anti-cancer drugs is often accompanied by unexpected side-effects induced by their cytotoxicity. Camptothecin (CPT, Figure 1B) is a potent anti-cancer agent used to treat various cancers [START_REF] Yang | Influence of supramolecular encapsulation of camptothecin by cucurbit[7]uril: reduced toxicity and preserved anti-cancer activity[END_REF] but it can be converted into an active lactone form and a toxic carboxylate analogue, thereby limiting its applicability.

Studies have shown that the structural changes of CPT can be limited by formation of supramolecular complexes with CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF]. Both in vitro and in vivo investigations have shown that the presence of CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] could alleviate the non-specific toxicity of CPT [START_REF] Yang | Influence of supramolecular encapsulation of camptothecin by cucurbit[7]uril: reduced toxicity and preserved anti-cancer activity[END_REF]. Zhang and co-authors have studied a supramolecular chemotherapy based on the formation of complexes between the anti-cancer drug oxaliplatin (OxPt, Figure 1B) and CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] [START_REF] Jeon | Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug[END_REF][START_REF] Chen | Supramolecular Chemotherapy: Cooperative Enhancement of Antitumor Activity by Combining Controlled Release of Oxaliplatin and Consuming of Spermine by Cucurbit[7]uril[END_REF]. Their study has demonstrated that the presence of CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] could significantly reduce the cytotoxicity of OxPt in vitro (on healthy colorectal NCM460 cells), and improve its anti-cancer activity by competitive binding with spermine which is overexpressed in some cancer cells such as HCT116 or HT-29 cells.

Besides common drugs, the toxicity of polymers can also be a serious source of concern. Polyethylenimine (PEI, Figure 1B) has been studied as a gene delivery vehicle [START_REF] Huang | Macrocycle-wrapped polyethylenimine for gene delivery with reduced cytotoxicity[END_REF]. However, the applicability of high molecular weight PEI (branched, 25 kDa) that have shown better gene delivery, is limited by their non-specific cytotoxicity. In this context, CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] was shown to significantly decrease the cytotoxicity of PEI most likely by multiple host binding [START_REF] Huang | Macrocycle-wrapped polyethylenimine for gene delivery with reduced cytotoxicity[END_REF]. Likewise, the supramolecular shielding strategy works also well with hexadimethrine bromide (HB, or polybrene Figure 1), a polycation that can neutralize heparin and control internal bleeding. However, its use can induce severe cases of blood coagulation raising major concerns for the lives of patients [START_REF] Huang | Alleviation of Polycation-Induced Blood Coagulation by the Formation of Polypseudorotaxanes with Macrocyclic Cucurbit[7]uril[END_REF]. CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] can complex each repeating unit of HB with a binding affinity Ka of (1.04±0.19)×10 7 M -1 . Both in vitro and in vivo tests showed that coagulation effects induced by HB can be significantly decreased by this supramolecular encapsulation strategy [START_REF] Huang | Alleviation of Polycation-Induced Blood Coagulation by the Formation of Polypseudorotaxanes with Macrocyclic Cucurbit[7]uril[END_REF].

Antidote for pesticide poisoning

The extensive utilization of pesticides in agriculture is a significant source of pollution and can cause severe harm to ecosystems or humans. For instance, the pesticide nereistoxin (NTX, Figure 1B) and its derivative thiocyclam (THI, Figure 1B) have shown non-selective teratogenic toxicities, tested for alleviation by formation of supramolecular complexes with CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] [START_REF] Yang | Constraining the Teratogenicity of Pesticide Pollution by a Synthetic Nanoreceptor[END_REF]. Relatively high binding constants of (1.4±0.15)×10 5 M -1 and (7.46±0.10)×10 5 M -1 for NTX and THI respectively, enabled assessing antidotal effects. In vivo tests performed on zebrafish embryos and larvae showed that CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] significantly constrained the teratogenicity of NTX and THI [START_REF] Yang | Constraining the Teratogenicity of Pesticide Pollution by a Synthetic Nanoreceptor[END_REF]. Another example is that of the toxic and famous pesticide paraquat (PQ), still responsible for serious troubles in public health [START_REF] Zhang | A Synthetic Receptor as a Specific Antidote for Paraquat Poisoning[END_REF]. Recently, the Wang's group has studied the antidotal effect of CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] on PQ toxicity both in vitro and in vivo (Figure 6) [START_REF] Zhang | A Synthetic Receptor as a Specific Antidote for Paraquat Poisoning[END_REF]. While a reduction of PQ's toxicity was noted previously in studies focused on PQ•CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] complexes as anti-cancer agents (Ka ~ 10 5 M -1 ) [START_REF] Chen | Cytotoxicity Regulated by Host-Guest Interactions: A Supramolecular Strategy to Realize Controlled Disguise and Exposure[END_REF], the Wang's group developed a new method to reverse PQ poisoning [START_REF] Zhang | A Synthetic Receptor as a Specific Antidote for Paraquat Poisoning[END_REF]. This work showed that CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] could significantly decrease PQ levels in plasma and major organs, and alleviate their adverse effects via oral administration. In addition, oral administration of CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] within 2 hours post-PQ ingestion could improve the survival rates of mice and extend their survival time, outperforming activated charcoal that is usually used for the treatment of PQ poisoning [START_REF] Zhang | A Synthetic Receptor as a Specific Antidote for Paraquat Poisoning[END_REF].

Finally, with the antidotal effect of CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF], the PQ•CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] complex can also potentially be used as a safer herbicide [START_REF] Zhang | An Eco-and User-Friendly Herbicide[END_REF].

Acyclic cucurbiturils

One of the key advantages of CB[n]s is their rigid structures, but this can also limit their use in certain cases.

Isaacs and co-authors have developed a series of flexible, clip-like CB[n]s known as acyclic cucurbit[n]uril-type congeners (acyclic CB[n]

) [START_REF] Ma | Acyclic cucurbit[n]uril molecular containers enhance the solubility and bioactivity of poorly soluble pharmaceuticals[END_REF]. Calabadion 1 and calabadion 2 (abbreviated CLBD1 and CLBD2, respectively, see Figure 2B) have a flexible C-shape structure that can grasp many guest molecules in water. These acyclic CB [n] have shown good biocompatibility and strong binding affinities toward a wide range of molecules [START_REF] Ma | Acyclic Cucurbit[n]uril-Type Molecular Containers Bind Neuromuscular Blocking Agents In Vitro and Reverse Neuromuscular Block In Vivo[END_REF][START_REF] Ma | Acyclic cucurbit[n]uril molecular containers enhance the solubility and bioactivity of poorly soluble pharmaceuticals[END_REF][START_REF] Ganapati | In Vitro selectivity of an acyclic cucurbit[n]uril molecular container towards neuromuscular blocking agents relative to commonly used drugs[END_REF],

including NMBAs such as rocuronium and cisatracurium [START_REF] Ma | Acyclic Cucurbit[n]uril-Type Molecular Containers Bind Neuromuscular Blocking Agents In Vitro and Reverse Neuromuscular Block In Vivo[END_REF][START_REF] Hoffmann | Calabadion: A New Agent to Reverse the Effects of Benzylisoquinoline and Steroidal Neuromuscular-blocking Agents[END_REF][START_REF] Haerter | Comparative Effectiveness of Calabadion and Sugammadex to Reverse Non-depolarizing Neuromuscular-blocking Agents[END_REF].

Reversal of neuromuscular blocking agents

In vivo studies have revealed that CLBD1 could accelerate the recovery of spontaneous breathing, and reduce the time required to reach a train-to-four ratio of 0.9 for rats (given rocuronium and cisatracurium), from minutes to seconds, outperforming the recommended neostigmine/glycopyrrolate treatment [START_REF] Hoffmann | Calabadion: A New Agent to Reverse the Effects of Benzylisoquinoline and Steroidal Neuromuscular-blocking Agents[END_REF]. On the other hand, rocuronium was shown to be 89-fold better complexed by CLBD2 (Ka = 3.4×10 9 M -1 ) than by sugammadex (Ka = 3.8×10 7 M -1 ). Accordingly, CLBD2 provided a better reversal effect than sugammadex in vivo [START_REF] Haerter | Comparative Effectiveness of Calabadion and Sugammadex to Reverse Non-depolarizing Neuromuscular-blocking Agents[END_REF].

Reversal of toxicity of Illicit drugs

More recently, Isaacs and co-authors further explored the potential of acyclic CB[n] derivatives as supramolecular antidotes. The complexation of various illicit drugs (methamphetamine, fentanyl, cocaine, ketamine, phencyclidine, morphine and hydromorphone, Figure 1B) by CLBD1, CLBD2, and other host molecules (CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF], C [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF]AS and HP-β-CD) was investigated. Among all hosts, CLBD2 showed a good binding affinity for methamphetamine (Ka = (4.3±1.0)×10 6 M -1 , Figure 7), enabling to reverse the hyperlocomotive activity of rats treated with methamphetamine [START_REF] Ganapati | Molecular Containers Bind Drugs of Abuse in Vitro and Reverse the Hyperlocomotive Effect of Methamphetamine in Rats[END_REF].

Pillararenes

As one of the latest series of host molecules discovered, pillar[n]arenes (PA[n]s) have experienced a rapid development during the past decade [START_REF] Ogoshi | Pillar-Shaped Macrocyclic Hosts Pillar[n]arenes: New Key Players for Supramolecular Chemistry[END_REF][83][START_REF] Murray | The aqueous supramolecular chemistry of cucurbit[n]urils, pillar[n]arenes and deep-cavity cavitands[END_REF][START_REF] Xiao | Advanced Functional Materials Constructed from Pillar[n]arenes[END_REF]. Many applications of PA[n]s have been reported. However, as is the case for most host molecules, water solubility was a key barrier impeding their biological applications. In 2012, Huang and co-workers prepared a water soluble pillar [START_REF] Audi | Ricin PoisoningA Comprehensive Review[END_REF]arene (WPA [START_REF] Audi | Ricin PoisoningA Comprehensive Review[END_REF], Figure 2B) with an excellent potential for biological applications [START_REF] Yu | A Water-Soluble Pillar[6]arene: Synthesis, Host-Guest Chemistry, and Its Application in Dispersion of Multiwalled Carbon Nanotubes in Water[END_REF]. The strong binding affinity of WPA [START_REF] Audi | Ricin PoisoningA Comprehensive Review[END_REF] for PQ (Ka = (1.02±0.10)×10 8 M - 1 ) suggested that WPA [START_REF] Audi | Ricin PoisoningA Comprehensive Review[END_REF] could be a potent antidote [START_REF] Yu | Pillar[6]arene/Paraquat Molecular Recognition in Water: High Binding Strength, pH-Responsiveness, and Application in Controllable Self-Assembly, Controlled Release, and Treatment of Paraquat Poisoning[END_REF].

Alleviation of cytotoxicity

This macrocycle was so used in a supramolecular chemotherapy approach to decrease the cytotoxicity of OxPt while improving its anti-cancer activity. The good binding affinity between WPA [START_REF] Audi | Ricin PoisoningA Comprehensive Review[END_REF] and OxPt in phosphate buffer at pH 7.4 and 37.0 °C enabled to decrease the cytotoxicity of OxPt [START_REF] Hao | Supramolecular Chemotherapy: Carboxylated Pillar[6]arene for Decreasing Cytotoxicity of Oxaliplatin to Normal Cells and Improving Its Anticancer Bioactivity Against Colorectal Cancer[END_REF][START_REF] Hao | Correction to "Supramolecular Chemotherapy: Carboxylated Pillar[6]arene for Decreasing Cytotoxicity of Oxaliplatin to Normal Cells and Improving Its Anticancer Bioactivity Against Colorectal Cancer[END_REF].

Reversal of neuromuscular blocking agents

Succinylcholine (Sch, Figure 1) is the only depolarizing NMBA that is widely used for rapid sequence induction in emergency rooms [START_REF] Zhang | Supramolecular therapeutics to treat the side effects induced by a depolarizing neuromuscular blocking agent[END_REF]. However, its use can be accompanied by severe side-effects, such as hyperkalemia and cardiac arrest. Sch can be complexed by SC [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF]A, CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] and WPA [START_REF] Audi | Ricin PoisoningA Comprehensive Review[END_REF] in vitro with respective association constants Ka Sch•C [START_REF] Cohen | Botulinum toxins: cosmetic and clinical applications[END_REF]AS ~ 10 4 M -1 , Ka Sch•CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] ~ 10 6 M -1 and Ka Sch•WPA [START_REF] Audi | Ricin PoisoningA Comprehensive Review[END_REF] ≈ 3.4×10 6 M -1 . Among these hosts, WPA [START_REF] Audi | Ricin PoisoningA Comprehensive Review[END_REF] exhibited excellent antidotal effects. In vivo studies showed that the encapsulation of Sch by WPA [START_REF] Audi | Ricin PoisoningA Comprehensive Review[END_REF] reduced the guest side-effects', such as the incidence of cardiac arrhythmia, high serum potassium levels, and muscular damage [START_REF] Zhang | Supramolecular therapeutics to treat the side effects induced by a depolarizing neuromuscular blocking agent[END_REF]. Inspired by the success of sugammadex, Stoikov and co-workers synthesized a water soluble PA [START_REF] Parreño | A synthetic biology approach for consistent production of plant-made recombinant polyclonal antibodies against snake venom toxins[END_REF],

namely WPA [START_REF] Parreño | A synthetic biology approach for consistent production of plant-made recombinant polyclonal antibodies against snake venom toxins[END_REF] (Figure 2B), containing similar side-chains as those of sugammadex, and aimed at achieving a better reversal effect for the use of rocuronium bromide. Although WPA [START_REF] Parreño | A synthetic biology approach for consistent production of plant-made recombinant polyclonal antibodies against snake venom toxins[END_REF] required a longer time than enabled by sugammadex for the recovery of muscle contraction after restriction by rocuronium, it still showed a great potential as a new kind of antidote [START_REF] Shurpik | Supramolecular neuromuscular blocker inhibition by a pillar[5]arene through aqueous inclusion of rocuronium bromide[END_REF]. The main properties of macrocycles as antidotes are summarized in Table 1.

Conclusion

In summary, we believe that the macrocyclic chemistry has entered in a gold era. The number of host compounds reported has never been so high and researchers are now strongly interested in testing rapidly new macrocycles for an also ever-increasing number of applications. starting with sugammadex, which is the initial host that has been developed to reverse the effects of NMBAs (Figure 8), other host molecules have started to be studied for their inhibition/reversal effects toward bioactive compounds.

As the sole clinically and commercially successful case, sugammadex still presents significant risks that have limited its extensive applications. But many host molecules such as cyclodextrins, pillararenes, cucurbiturils, and acyclic cucurbituril derivatives have shown a real potential for the next generation supramolecular antidotes, they can additionally be functionalized to improve affinity and selectivity, and new host molecules are periodically described [START_REF] Liu | Surveying macrocyclic chemistry: from flexible crown ethers to rigid cyclophanes[END_REF][START_REF] Yang | Naphthotubes: Macrocyclic Hosts with a Biomimetic Cavity Feature[END_REF]. In the definition given for "Antidotes" by the Encyclopaedia Britannica, it is mentioned that such a substance can be able to: "keep … (a poison) … from fitting a receptor at its site of action; or binding to a receptor to prevent the poison's binding there, blocking its action". With the emergence of protein binding by macrocycles such as calixarenes or cucurbiturils [START_REF] Chinai | Molecular Recognition of Insulin by a Synthetic Receptor[END_REF][START_REF] Rennie | Auto-regulated Protein Assembly on a Supramolecular Scaffold[END_REF], there is only one step to imagine macrocycles able to target proteins expressed on the surface of viruses, thereby reducing virus binding and impeding early stages of viral infection, something highly topical after the emergence of the pandemic SARS-CoV-2 virus. There still may be a long way to reach that purpose, but macrocycles and analogous host compounds have already opened fascinating perspectives as supramolecular antidotes.

Abbreviations

  Abbreviations

  .A. refers to not available. PBS refers to phosphate buffer saline. R.T. refers to room temperature. HEPES refers to 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid buffer.

Figure 1 .

 1 Figure 1. Structures of toxic compounds discussed in this review. Examples of natural toxins (A) present in

Figure 2 .

 2 Figure 2. Structures of host molecules used as antidotes. Principle of poison (or drug) capture (A) by synthetic

Figure 3 .

 3 Figure 3. Proposed mechanism for the recovery of natural partners of nAChR membrane proteins by

Figure 4 .

 4 Figure 4. Plasma concentration of PQ against time after oral administrations of PQ, inclusion complex, and

Figure 7 .

 7 Figure 7. Capture of methamphetamine by CLBD2. Reprinted from ref. [81]. Copyright 2017 John Wiley & Sons,

Figure 8 .

 8 Figure 8. Timeline highlighting selected key developments in supramolecular chemistry and prime macrocyclic

Table 1 .

 1 Effects of supramolecular antidotes toward toxic compounds.

	Molecule	Toxicity	Antidote	Effect of Antidote	Binding Affinity	Ref.
					[Solvent/pH/Temperat
					ure (℃)]
	Rocuronium	Neurotoxicity	Sugammadex	Accelerate recovery from	(1.05±0.16)×10 7 M -1	[29]
				anaesthesia
					[50mM PBS/7.0/25]
			CLBD1	Accelerate recovery from	(8.4±0.9)×10 6 M -1	[79]
				anaesthesia
					[N.A./N.A./N.A.]
			CLBD2	Accelerate recovery from	3.4×10 9 M -1	[80]
				anaesthesia
					[N.A./7.4/25]

Acknowledgements 15

The Science and Technology Development Fund (FDCT), Macau SAR (Grant No.: 020/2015/A1 and 0007/2020/A), and University of Macau (Grant No.: MYRG2019-00059-ICMS) are gratefully acknowledged for providing financial support to this work. DB acknowledges CNRS and Aix-Marseille University for continuous support.

Competing interests

There is no conflict of interest to report. [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] as treatment in PQ detoxification. CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] is orally administered after PQ ingestion. In the stomach or intestine, PQ is trapped by CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF], preventing further damages to the intestines and reducing the absorption and tissue distribution of PQ. Most of the pesticide will be excreted as PQ•CB [START_REF] Amabilino | Supramolecular chemistry anniversary[END_REF] complexes. Reprinted from ref. [START_REF] Zhang | A Synthetic Receptor as a Specific Antidote for Paraquat Poisoning[END_REF]. Copyright 2019 Ivyspring.