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Helical folding of a carbazole–pyridine oligomer generates a tweezer-type binding cavity which allows for the intercalation of a naphthalenediimide guest.

We previously identified KS40008 (4-(3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzene-1,2-diol), a novel inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase family (DYRK) 1A/B, which exhibited high enzymatic activity and cell proliferation-inhibitory effects in colorectal cancer (CRC) cell lines. In the present study, we aimed to elucidate the antitumor mechanisms of KS40008.To assess the cytotoxicity of KS40008, we utilized a human cell line and organoid model and performed a CCK-8 assay and real-time cell analysis. Mitochondrial function was determined through mitochondrial staining, mito-stress test, and glycolysis test. In addition, we investigated the mechanisms of cancer cell death induced by KS40008 through immunoblotting, real-time quantitative polymerase chain reaction, reactive oxygen species staining, and immunofluorescence staining.KS40008 exhibited significant cytotoxicity in CRC and non-CRC cell lines, and organoid models compared to 5-fluorouracil, a conventional chemotherapeutic drug. Moreover, KS40008-induced inhibition of DYRK1A/B led to mitochondrial dysfunction and endoplasmic reticulum stress, promoting autophagic cancer cell death.KS40008 exerts antitumor activity through the inhibition of DYRK1A/B. Here, we demonstrated a mechanism by which KS40008 affects endoplasmic reticulum stress-mediated autophagy through the induction of mitochondrial stress, leading to cytotoxicity in CRC.

Aromatic helical receptors P-1 and P-2 were slightly modified by aerobic oxidation to afford new receptors P-7 and P-8 with right-handed helical cavities. This subtle modification induced significant changes in the binding properties for chiral guests. Specifically, P-1 was reported to bind d-tartaric acid (Ka =35500 M-1 ), used as a template, much strongly than l-tartaric acid (326 M-1 ). In contrast, its modified receptor P-7 exhibited significantly reduced affinities for d-tartaric acid (3600 M-1 ) and l-tartaric acid (125 M-1 ). More dramatic changes in the affinities and selectivities were observed for P-2 and P-8 upon binding of polyol guests. P-2 was determined to selectively bind d-sorbitol (52000 M-1 ) over analogous guests, but P-8 showed no binding selectivity: d-sorbitol (1890 M-1 ), l-sorbitol (3330 M-1 ), d-arabitol (959 M-1 ), l-arabitol (4970 M-1 ) and xylitol (4960 M-1 ) in 5% (v/v) DMSO/CH2 Cl2 at 25±1 °C. These results clearly demonstrate that even subtle post-modifications of synthetic receptors may significantly alter their binding affinities and selectivities, in particular for guests of long and flexible chains.

As a synthetic model for intra-protein interactions that reinforce binding affinities between proteins and ligands, the energetic interplay of binding and folding was investigated using foldamer-based receptors capable of adopting helical structures. The receptors were designed to have identical hydrogen-bonding sites for anion binding but different aryl appendages that simply provide additional π-stacking within the helical backbones without direct interactions with the bound anions. In particular, the presence of electron-deficient aryl appendages led to dramatic enhancements in the association constant between the receptor and chloride or nitrate ions, by up to three orders of magnitude. Extended stacking within the receptor contributes to the stabilization of the entire folding structure of complexes, thereby enhancing binding affinities.

As DYRK1A and 1B inhibitors, 1H-pyrazolo[3,4-b]pyridine derivatives were synthesized. Mostly, 3-aryl-5-arylamino compounds (6) and 3,5-diaryl compounds (8 and 9) were prepared and especially, 3,5-diaryl compound 8 and 9 showed excellent DYRK1B inhibitory enzymatic activities with IC50 Values of 3–287 nM. Among them, 3-(4-hydroxyphenyl), 5-(3,4-dihydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine (8h) exhibited the highest inhibitory enzymatic activity (IC50 = 3 nM) and cell proliferation inhibitory activity (IC50 = 1.6 µM) towards HCT116 colon cancer cells. Also compound 8h has excellent inhibitory activities in patient-derived colon cancer organoids model as well as in 3D spheroid assay model of SW480 and SW620. The docking study supported that we confirmed that compound 8h binds to DYRK1B through various hydrogen bonding interactions and hydrophobic interactions.

We described a silver(I)-mediated intramolecular oxidative C–H amination that enables the construction of assorted 1H-indazoles that are widely applicable in medicinal chemistry. The developed amination was found to be efficient for the synthesis of a variety of 3-substituted indazoles that are otherwise difficult to be synthesized by other means of C–H aminations. Preliminary mechanistic studies suggested that the current amination proceeds via single electron transfer (SET) mediated by Ag(I) oxidant.

Redox-active metal ions are pivotal for rapid metabolism, proliferation, and aggression across cancer types, and this presents metal chelation as an attractive cancer cell-targeting strategy. Here, we identify a metal chelator, KS10076, as a potent anti-cancer drug candidate. A metal-bound KS10076 complex with redox potential for generating hydrogen peroxide and superoxide anions induces intracellular reactive oxygen species (ROS). The elevation of ROS by KS10076 promotes the destabilization of signal transducer and activator of transcription 3, removes aldehyde dehydrogenase isoform 1-positive cancer stem cells, and subsequently induces autophagic cell death. Bioinformatic analysis of KS10076 susceptibility in pan-cancer cells shows that KS10076 potentially targets cancer cells with increased mitochondrial function. Furthermore, patient-derived organoid models demonstrate that KS10076 efficiently represses cancer cells with active KRAS, and fluorouracil resistance, which suggests clinical advantages.

Two indolocarbazole-naphthyridine foldamers 2 and 3 that fold into helical conformations were prepared. The 4-(N,N-dimethylamino)pyridine (DMAP) moiety was introduced at one end of the foldamer strands to develop foldamer-based catalysts for the site-selective acylation of polyols. These foldamers adopt helical conformations containing internal cavities capable of binding octyl β-d-glucopyranoside. The association constants were determined to be 1.9 (±0.1)×105 M-1 for 2 and 2.1 (±0.1)×105 M-1 for 3 in CH2 Cl2 at 25 °C. In the presence of DMAP, 2 or 3 as the catalysts, octyl β-d-glucopyranoside was subjected to acetylation under identical reaction conditions. The DMAP-catalysed reaction afforded the random distribution of the monoacetylates (6-OAc : 4-OAc : 3-OAc : 2-OAc=33 : 24 : 41 : 2). In contrast, foldamers 2 and 3 led to the predominant formation of 6-OAc. The relative distributions were estimated to be 6-OAc : 4-OAc : 3-OAc=88 : 4 : 6 : ∼0 with 2 and 6-OAc : 4-OAc : 3-OAc : 2-OAc=90 : 3 : 6 : 1 with 3.

Indolocarbazole-Pyridine (IP) hybrid foldamers have been known to adopt a helical conformation with an internal tubular cavity wherein water molecules are tightly packed via the formation of multiple cooperative hydrogen bonds. In order to develop IP foldamer-based receptors for ions and molecules other than water molecules, we herein prepare two modified IP foldamers 2 and 3 that contain a pyrrole and an inverted pyridine in the middle of the strands, respectively, instead of the original pyridine unit. Such site-specific modification significantly disrupts the hydrogen-bonding network between the entrapped water molecules and the interior of the cavity, thus allowing for binding two dihydrogenphosphate ions as a cyclic dimer inside the cavity as demonstrated by 1H NMR spectroscopy and X-ray crystal structure analysis. The crystal structures of the two complexes (H2PO4−)2 ⊂ 2 and (H2PO4−)2 ⊂ 3 are very similar to each other, with twelve hydrogen bonds between the bound dihydrogenphosphate dimer and the interior functional groups, indolocarbazole NH protons, pyridine nitrogen atoms and terminal OH protons in the helical tubular cavity.

A series of indolocarbazole-pyridine (IP) hybrid foldamers containing chiral residues at multiple different positions were prepared to reveal the matched and mismatched phenomena of local stereocenters on the induction of helical bias. These foldamers adopted stable helical conformations, thus affording well-resolved separate sets of 1H NMR signals for right- (P) and left-handed (M) helices in water saturated organic solvents such as toluene and dichloromethane. The ratios of P- and M-helices were determined by integrating the 1H NMR signals, in combination with the molar circular dichroism (Δe) and optical rotation ([α]D) values. The degree of helical bias was larger in the IP foldamer bearing chiral residues at the termini relative to those at the pyridine side chains, but the preferred helix orientation was opposite to each other. Foldamers 5(SS)t(SSS)py and 6(RR)t(SSS)py with chiral residues at five different positions demonstrated the matched and mismatched phenomena of local stereocenters in 6(RR)t(...

An indolocarbazole–naphthyridine hybrid oligomer capable of adopting a stable helical conformation was prepared, and its folding properties were thoroughly studied in the solid state and in solution. As a result of folding, a hydrophilic cavity was generated inside the helix wherein monosaccharides were able to be encapsulated in the order of glucose (9.6 × 104 M–1) > galactose (1.0 × 104 M–1) ≫ mannose (∼0) in 10% (v/v) DMSO/CH2Cl2.

Highly effective and safe drugs for the treatment of neuropathic pain are urgently required and it was shown that blocking T-type calcium channels can be a promising strategy for drug development for neuropathic pain. We have developed pyrrolidine-based T-type calcium channel inhibitors by structural hybridization and subsequent assessment of in vitro activities against Cav3.1 and Cav3.2 channels. Profiling of in vitro ADME properties of compounds was also carried out. The representative compound 17h showed comparable in vivo efficacy to gabapentin in the SNL model, which indicates T-type calcium channel inhibitors can be developed as effective therapeutics for neuropathic pain.

The helical handedness excess of an indolocarbazole–pyridine hybrid oligomer capable of folding into a stable helical structure was achieved up to 96% by rational modification of terminal chiral residues.

SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2) is a lipid phosphatase that produce phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) from phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3), and is involved in many diseases such as neurodegenerative diseases. A recent report demonstrating that SHIP2 inhibition decreased tau hyperphosphorylation induced by amyloid β and rescued memory impairment in a transgenic Alzheimer's disease mouse model indicates SHIP2 can be a promising therapeutic target for Alzheimer's disease. In the present study, we have developed novel, potent SHIP2 inhibitors by extensive structural elaboration of crizotinib discovered from a high-throughput screening. Our representative compound 43 potently inhibited SHIP2 activity as well as GSK3β activation in HT22 neuronal cells. It was also shown that 43 has favorable physicochemical properties, especially high brain penetration. Considering SHIP2 is one of key signal mediators for tau hyperphosphorylation, our potent SHIP2 inhibitor 43 may function as a promising lead compound for the treatment of Alzheimer's disease.

A new double-stranded dinuclear helicate that displays conformational switching in response to temperature was prepared by self-assembly of an aromatic helical foldamer and dichloropalladium(ii). The relative populations of the two helicate conformers, syn-anti and syn-syn, were demonstrated to be reversibly modulated through temperature control.

Through variation of the central pyridine in an indolocarbazole-pyridine hybrid foldamer, the kinetic stabilities of helical conformations were determined and compared based on the inter-conversion rates of P and M helical isomers.

The treatment of neuropathic pain is one of the urgent unmet medical needs and T-type calcium channels are promising therapeutic targets for neuropathic pain. Several potent T-type channel inhibitors showed promising in vivo efficacy in neuropathic pain animal models and are being investigated in clinical trials. Herein we report development of novel pyrrolidine-based T-type calcium channel inhibitors by pharmacophore mapping and structural hybridisation followed by evaluation of their Cav3.1 and Cav3.2 channel inhibitory activities. Among potent inhibitors against both Cav3.1 and Cav3.2 channels, a promising compound 20n based on in vitro ADME properties displayed satisfactory plasma and brain exposure in rats according to in vivo pharmacokinetic studies. We further demonstrated that 20n effectively improved the symptoms of neuropathic pain in both SNL and STZ neuropathic pain animal models, suggesting modulation of T-type calcium channels can be a promising therapeutic strategy for the treatment of neuropathic pain.

Of the bisurea compounds linked through trans- and cis-benzanilide spacers, the cis-amide derivatives were found to be effective in chloride transport, using which a stimuli-responsive mobile carrier was devised.

Eight carbazole-based molecular tweezers (CMTs) were designed and synthesized for application in the discrimination of heavy metal ions. All CMT solutions in MeCN were transparent, but exhibited strong deep blue or sky blue fluorescence emission upon UV irradiation. The electronic absorptions of CMTs appeared mainly in the UV region. The CMTs exhibited different fluorescence response patterns upon the addition of various transition metal ions. The principal component analysis (PCA) and linear discriminant analysis (LDA) exhibited clear clustering of data points within the same metal ions and successful dispersion of data clusters. The influence of anionic species on the fluorescence emission of CMTs was almost negligible. Therefore, the chemometric analysis allowed for successful discrimination of 18 heavy metal ions.

Recovery of mitochondrial dysfunction has gained increasing attention as an alternative therapeutic strategy for Alzheimer's disease (AD). Recent studies suggested that the 18 kDa mitochondrial translocator protein (TSPO) has the potential to serve as a drug target for the treatment of AD. In this study, we generated a structure-based pharmacophore model and virtually screened a commercial library, identifying SVH07 as a virtual hit, which contained a tricyclic core structure, thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine group. A series of SVH07 analogues were synthesized and their effects on the mitochondrial membrane potential and ATP production were determined by using neuronal cells under Aβ-induced toxicity. Among these analogues, compound 26 significantly recovered mitochondrial membrane depolarization and ATP production. In vitro binding assays indicated that SVH07 and 26 showed high affinities to TSPO with the IC50 values in a nanomolar range. We believe that compound 26 is a promising lead compound for the development of TSPO-targeted mitochondrial functional modulators with therapeutic potential in AD.

An indolocarbazole dimer, containing chiral urea appendages, that adopts a helically folded conformation by intramolecular hydrogen bonds as proven by 1H NMR and circular dichroism (CD) spectroscopy has been prepared. Owing to the preferential formation of one helical conformer, strong CD signals appear in relatively non-polar solvents such as chloroform (CHCl3) and dichloromethane (CH2Cl2) but the signal is negligible in dimethyl sulfoxide (DMSO). In addition, the optical rotation of the dimer is highly sensitive to the polarity of solvents. For example, the magnitude of the specific rotation ([α]D) is − 934° in CH2Cl2 and − 657° in CHCl3 but it is only − 75° in DMSO. These observations suggest that the dimer folds to a helical structure by intramolecular hydrogen bonds in relatively non-polar solvents but exists in an unfolded extended conformation in polar solvents such as DMSO. The dimer strongly binds anions such as chloride, acetate and sulfate by multiple hydrogen bonds. In addition, anion binding ...

An indolocarbazole dimer that contains aldehyde groups at both ends was prepared by connecting two monomeric units through a rod-like 1,4-butadiynyl spacer. Upon mixing with chiral 1,2-diamines at room temperature, the dimer was in situ converted to the corresponding cyclic diimines in the presence of tetrabutylammonium acetate as a template. The resulting diimines fold to helical conformations of right-handed (P) or left-handed (M) orientations, depending on the absolute stereochemistries of chiral 1,2-diamines. The patterns and intensities of the CD spectra can be used to determine the absolute configurations and enantiomeric excesses of chiral 1,2-diamines.

An indolocarbazole dimer with the urea functional group was prepared as an anion receptor which contained eight NH hydrogen bonds donors. Two indolocarbazole units were coupled through a butadiynyl linker to allow for helical folding of the resulting dimer by intramolecular hydrogen bonding and dipole–dipole attractions as proven in the 1H NMR spectroscopy. The dimer was found to bind anions (Cl− , Br− , N3 − , AcO− , and ) by multiple hydrogen bonds in 10% (v/v) MeOH–acetone, showing high selectivity for sulphate ion. The 1H NMR spectra clearly demonstrated that only indolocarbazole NH protons were involved in the hydrogen bonding with small anions such as chloride, but all of the existing indolocarbazole and urea NHs participated in the hydrogen bonding with sulphate ion. This difference in the binding mode might be responsible for the high affinity and selectivity towards sulphate ion.

Adopting the concept of procarrier for the first time, we demonstrated the controlled transport of chloride ions across lipid and cellular membranes. Procarriers containing highly hydrophilic appendages were initially inactive due to the lack of their partitioning into lipophilic membranes but were activated to transport chloride ions in the presence of specific enzymes that were able to hydrolyze off the appendages to generate an active carrier under specific conditions. Namely, the procarrier with an ester-bond-linked appendage was most activated by an esterase (PLE) at pH = 7.4, whereas the procarrier with a glycosyl-bond-linked appendage was activated only by a glycosylase (AOG) under slightly acidic conditions (pH = 5.5–6). In addition to controlling chloride transport, hydrophilic appendages greatly increase the water solubility of the procarrier, which may improve the deliverability of a hydrophobic active carrier into a plasma membrane.

Using a series of diphenylureas capable of folding to helical conformations, the binding trends have been compared between two anions of different sizes, chloride and sulfate. The binding constant for the sulfate ion steadily increases from monomer to pentamer as the chain length increases, but for the chloride ion it increases up until the trimer and then reaches a plateau.

Chiral organic anions such as camphorsulfonates and cAMP give rise to the preferential formation of a one-handed helix of an indolocarbazole foldamer, thus inducing characteristic circular dichroic (CD) signals. Moreover, the on and off switching of the chiroptical signal can be operated by acid and base chemistry which efficiently controls the association and dissipation of the foldamer and cAMP.

A number of indolocarbazole-based anion receptors were prepared and their anion-binding behaviors were characterized in solution and in the solid state. First, chain-length-dependent binding affinities of chloride ion were revealed using a series of indolocarbazoles that consisted of one to four indolocarbazole units. The binding affinities were steadily enhanced from monomer to dimer, then to trimer by Gibb’s free energy (–∆∆G) = 2.4 ± 0.1 kcal/mol, and then nearly saturated. Second, a water-soluble trimer folded to generate an internal helical cavity with six convergent NHs, wherein small halides bound in water in the order of Cl– (65 M–1) > F– (46 M–1), and Br– (19 M–1). Third, X-ray crystal structures clearly proved helical folding of a trimer in the presence of sulfate ion, in which left- and right-handed helices stacked alternatively. It was also shown that the selectivity of anion binding could be varied by the modification of the spacer groups connecting indolocarbazole units. Finally, we prepared chiral indolocabazole dimers that adopted helical structures by intramolecular hydrogen bonds and displayed complete inversion of the helical sense upon anion binding. The dimers gave characteristic optical readouts in a reversible manner according to chemical stimuli, thus functioning as chirooptical molecular switches.

A series of isoxazol-indolin-2-one was designed for GSK-3 inhibitors as novel anticancer agents based on their binding mode analysis in GSK-3 crystal structure. Total 21 compounds were synthesized and evaluated for their inhibitory activity against two tumor cell lines (DU145 and HT29). Most of the synthesized compounds were potent with above 80% inhibitory activity at 100 , and several compounds were examined for inhibitory activity against GSK-3. Among them, 15(Z) (=H, =3-Cl-phenyl) was most active with 78% inhibition of tumor cell line (HT29) at 20 and 72% inhibition of GSK-3 at 20 .

A colorimetric anion receptor based on an indole scaffold has been synthesized by incorporating an azobenzene chromophore to the 5-position of indole. The receptor binds anions by hydrogen bonds which are effectively transmitted through resonance to the chromophore to give rise to color changes. The cyanide ion induced a pronounced color change from light yellow to reddish orange, but less intense or negligible changes were observed with the other anions examined here.

Liposomes as one of the efficient drug carriers have some shortcomings such as their relatively short blood circulation time, fast clearance from human body by reticuloendothelial system (RES) and limited intracellular uptake to target cells. In this study, polyethylene glycol (PEG)-complexed cationic liposomes (PCL) were prepared by ionic complex of cationically charged liposomes with carboxylated polyethylene glycol (mPEG-COOH). The cationic liposomes had approximately 98.6+/-1.0 nm of mean particle diameter and 45.5+/-1.1 mV of zeta potential value. While, the PCL had 110.1+/-1.2 nm of mean particle diameter and 18.4+/-0.8 mV of zeta potential value as a result of the ionic complex of mPEG-COOH with cationic liposomes. Loading efficiency of model drug, doxorubicin, into cationic liposomes or PCL was about 96.0+/-0.7%. Results of intracellular uptake evaluated by flow cytometry and fluorescence microscopy studies showed higher intracellular uptake of PCL than that of Doxil. In addition, in vitro cytotoxicity of PCL was comparable to cationic liposomes. In pharmacokinetic study in rats, PCL showed slightly lower plasma level of DOX than that of Doxil. In vivo antitumor activity of DOX-loaded PCL was comparable to that of Doxil against human SKOV-3 ovarian adenocarcinoma xenograft rat model. Consequently, the PCL, of which surface was complexed with PEG by ionic complex may be applicable as drug delivery carriers for increasing therapeutic efficacy of anticancer drugs.

Oligoindole-based chiral foldamers have been synthesized by incorporating (S)- or (R)-1-phenylethylamine to both ends of the tetraindole scaffold. The oligoindoles fold into a helical conformation upon binding an anion by hydrogen bonds, which gives rise to an induced circular dichroism (CD) signal of large amplitude, implying the preferential formation of one helical isomer over another. Theoretical calculations suggest that the (P)-helix of the (S,S)-oligoindole 8a be more energetically stable than the corresponding (M)-helix.

Anionic lipid nanoparticles (LNPs) are a lipid-based encapsulation system for poorly water-soluble compounds. Paclitaxel-loaded lipid nanoparticles were prepared by spontaneous emulsification and solvent evaporation (SESE) method with phospholipid, cholesterol, anionic lipids and pacltiaxel. The stability of anionic LNPs was enhanced after lyophilization. Mean particle size and zeta potential of anionic LNPs were measured by electrophoretic light scat- tering spectrophotometer and drug loading efficiency was evaluated by HPLC. The mean particle size was about 110 nm and loading efficiency was around 70%. DPPA was very efficient for increasing stability because it leads to coulombic repulsive forces of particles. According to cholesterol ratios increased of mean particle size and decreased of drug loading efficiency in the lipid compositions. Also, the low cytotoxicity was observed by MTT assay against B16F10 cells. Anionic LNPs may be a promising drug carrier for the poorly water-soluble drugs.

Indole-based synthetic receptors which bind anions by multiple hydrogen bonds in organic solvents have been prepared. The biindole scaffold bearing two good hydrogen bond donors of indole NHs has been used as a molecular building block to construct the receptors. Incorporation of more hydrogen bond donors or acceptors increases the binding strength and selectivity toward a specific ion. Two macrocycles having different sizes of the internal cavities have been also synthesized, and their binding properties have been compared. Two macrocycles display distinct binding modes with polyatomic anions such as azide, as unequivocally proven by X-ray crystal structures. Finally, a series of oligoindoles containing four, six, and eight indoles have been prepared by Sonogashira reactions. The oligoindoles fold into helical structures upon binding with chloride. The binding affinities of the oligoindoles with chloride increase with increasing of the chain length, which provides an additional evidence for helical folding of the complexes.

A new biindolyl scaffold, 7,7′-diamino-2,2′-biindolyl, 2 was efficiently synthesized and modified into anion receptors 9 and 10 with extended hydrogen bond donors. The receptor 9 possesses two indole NHs and two amide NHs, while 10 contains two indole NHs and four urea NHs. The receptors 9 and 10 bind oxoanions such as phosphates and carboxylates by multiple hydrogen bonds in DMSO, both of which bind two or three orders of magnitudes higher than does a reference molecule 8 with only two indole NHs. In addition, binding affinities of 10 with a series of dicarboxylates were also investigated, showing the association constants in between 1.6 × 105 M− 1 (malonate) and 8.1 × 105 M− 1 (adipate) in 10% (v/v) MeOH/DMSO at 22 ± 1°C.

A series of indolocarbazole-pyridine (IP) oligomers were prepared that fold into helical conformations, and their folding features in solution and in the solid state were revealed. Helical folding of these IP foldamers is induced by dipolar interactions through the ethynyl bond and π-stacking between two repeating units. Upon helical folding, (1)H NMR signals of aromatic protons were significantly shifted upfield by Δδ = 0.5-2.2 ppm. In addition, hypochromic shifts and fluorescence quenching were observed in the absorption and emission spectra. X-ray crystal structures clearly demonstrated that IP foldamers folded to helical structures with cylindrical internal cavities wherein 3 or 5 water molecules were occupied by hydrogen-bonding interactions in a 1-D array, reminiscent of transmembrane water channels, called aquaporins.