Recent advances in the modulation of amyloid protein aggregation using the supramolecular host-guest approaches.

Misfolding of proteins is associated with many incurable diseases in human beings. Understanding the process of aggregation from monomers to fibrils, the characterization of all intermediate species, and the origin of toxicity is very challenging. Extensive research including computational and experimental shed some light on these tricky phenomena.

Small molecule-based fluorescent probes for the detection of α-Synuclein aggregation states.

The formation of aggregates due to protein misfolding is encountered in various neurodegenerative diseases. α-Synuclein (α-Syn) aggregation is linked to Parkinson's disease (PD). It is one of the most prevalent neurodegenerative disorders after Alzheimer's disease.

Inhibition of Amyloid Protein Aggregation Using Selected Peptidomimetics.

Aberrant protein aggregation leads to the formation of amyloid fibrils. This phenomenon is linked to the development of more than 40 irremediable diseases such as Alzheimer's disease, Parkinson's disease, type 2 diabetes, and cancer. Plenty of research efforts have been given to understanding the underlying mechanism of protein aggregation, associated toxicity, and the development of amyloid inhibitors.

Cucurbit[7]uril Inhibits Islet Amyloid Polypeptide Aggregation by Targeting N Terminus Hot Segments and Attenuates Cytotoxicity.

Invited for the cover of this issue is the group of Prof. Hamilton at New York University. The image depicts how cucurbit[7]uril inhibits islet amyloid polypeptide self-assembly that rescues rat insulinoma cells (a pancreatic β-cell model) from assembly-associated cytotoxicity.

Cucurbit[7]uril Inhibits Islet Amyloid Polypeptide Aggregation by Targeting N Terminus Hot Segments and Attenuates Cytotoxicity.

Two "hot segments" within an islet amyloid polypeptide are responsible for its self-assembly, which in turn is linked to the decline of β-cells in type 2 diabetes (T2D). A readily available water-soluble, macrocyclic host, cucurbit[7]uril (CB[7]), effectively inhibits islet amyloid polypeptide (IAPP) aggregation through ion-dipole and hydrophobic interactions with different residues of the monomeric peptide in its random-coil conformation. A HSQC NMR study shows that CB[7] likely modulates IAPP self-assembly by interacting with and masking major residues present in the "hot segments" at the N terminus.

Improving Structural Stability and Anticoagulant Activity of a Thrombin Binding Aptamer by Aromatic Modifications.

The thrombin binding aptamer (TBA) is a 15-mer DNA oligonucleotide (5'-GGT TGG TGT GGT TGG-3'), that can form a stable intramolecular antiparallel chair-like G-quadruplex structure. This aptamer shows anticoagulant properties by interacting with one of the two anion binding sites of thrombin, namely the fibrinogen-recognition exosite. Here, we demonstrate that terminal modification of TBA with aromatic fragments such as coumarin, pyrene and perylene diimide (PDI), improves the G-quadruplex stability.

The helical supramolecular assembly of oligopyridylamide foldamers in aqueous media can be guided by adenosine diphosphates.

A metal-free and achiral tri-pyridylamide foldamer, DM 11, containing a critical naphthalimide side chain self-assembles in a left-handed helical manner in the presence of chiral adenosine phosphates, under physiological conditions. Surprisingly, a very high degree of helicity in the foldamer assemblies was observed with ADP compared to other nucleoside phosphates, including ATP.

Sub-stoichiometric inhibition of IAPP aggregation: a peptidomimetic approach to anti-amyloid agents.

Membrane-catalysed misfolding of islet amyloid polypeptide is associated with the death of β-cells in type II diabetes (T2D). Most active compounds so far reported require high doses for inhibition of membrane bound IAPP fibrillation. Here, we describe a naphthalimide-appended oligopyridylamide-based α-helical mimetic, , for targeting membrane bound IAPP.

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function.

Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer's disease and type II diabetes, identified a tripyridylamide, ADH-6, that abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD.

Peptidomimetic-Based Vesicles Inhibit Amyloid-β Fibrillation and Attenuate Cytotoxicity.

An interruption in Aβ homeostasis leads to the deposit of neurotoxic amyloid plaques and is associated with Alzheimer's disease. A supramolecular strategy based on the assembly of peptidomimetic agents into functional vesicles has been conceived for the simultaneous inhibition of Aβ fibrillation and expedited clearance of Aβ aggregates. Tris-pyrrolamide peptidomimetic, ADH-353, contains one hydrophobic -butyl and two hydrophilic -propylamine side chains and readily forms vesicles under physiological conditions.

Selected peptide-based fluorescent probes for biological applications.

To understand the molecular interactions, present in living organisms and their environments, chemists are trying to create novel chemical tools. In this regard, peptide-based fluorescence techniques have attracted immense interest. Synthetic peptide-based fluorescent probes are advantageous over protein-based sensors, since they are synthetically accessible, more stable, and can be easily modified in a site-specific manner for selective biological applications.

A Selective Cucurbit[8]uril-Peptide Beacon Ensemble for the Ratiometric Fluorescence Detection of Peptides.

A convenient supramolecular strategy for constructing a ratiometric fluorescent chemosensing ensemble, consisting of a macrocyclic host (cucurbit[8]uril CB[8]), and a pyrene-tagged amphiphilic peptide beacon (AP 1), is reported. AP 1 unfolds upon encapsulation of the pyrene termini into the hydrophobic CB[8] cavity. This changes pyrene excimer to monomer emission.

Arginine mimetic appended peptide-based probes for fluorescence turn-on detection of 14-3-3 proteins.

14-3-3 proteins are adaptor elements in intracellular signaling pathways. Recently, this protein family has been identified as a relevant therapeutic target involved in many human diseases. Therefore, identification of 14-3-3 proteins in biological systems is very important.

α-Helix-Mimetic Foldamers for Targeting HIV-1 TAR RNA.

An oligopyridylamide-based foldamer approach has been employed to target HIV TAR RNA-TAT assembly as a model system to study RNA-protein interactions. The oligopyridylamide scaffold adopts a constrained conformation which presents surface functionalities at distinct spatial locations and mimic the chemical features of the secondary structure of proteins. We have designed a library of oligopyridylamides containing diverse surface functionalities which mimic the side chain residues of the TAT protein domain.

Correction: A metal-free fluorescence turn-on molecular probe for detection of nucleoside triphosphates.

Correction for 'A metal-free fluorescence turn-on molecular probe for detection of nucleoside triphosphates' by Debabrata Maity et al., Chem. Commun.

A metal-free fluorescence turn-on molecular probe for detection of nucleoside triphosphates.

We report a fluorescence probe 1, which contains a naphthalimide fluorophore with two symmetric peptidic arms equipped with a tailor-made anion-binding motif, the guanidiniocarbonyl pyrrole moiety, for the detection of nucleoside triphosphates. Upon binding to nucleoside triphosphates, especially ATP, 1 shows significant turn-on fluorescence response. Probe 1 can also be applied for the imaging of ATP in cells.

Fluorescent Peptide Beacons for the Selective Ratiometric Detection of Heparin.

Heparin is extensively used as an anticoagulant drug during surgery. Two fluorophore-functionalized cationic oligopeptides HS 1 and HS 2 were developed to monitor heparin ratiometrically in aqueous media. Upon binding to heparin, HS 1 and HS 2 undergo a conformational change from an open form to a folded form, which leads to a distinct change in the fluorescence properties.

A FRET-enabled molecular peptide beacon with a significant red shift for the ratiometric detection of nucleic acids.

A cationic molecular peptide beacon NAP1 functionalized with a fluorescence resonance energy transfer-pair at its ends allows the ratiometric detection of ds-DNA with a preference for AT rich sequences. NAP1 most likely binds in a folded form into the minor groove of ds-DNA, which results in a remarkable change in its fluorescence properties. As NAP1 exhibits quite low cytotoxicity, it can also be used for imaging of nuclear DNA in cells.

Can Postoperative Nutrition be Favourably Maintained by Oral Diet in Patients with Emergency Temporary Ileostomy? A Tertiary Hospital Based Study.

Introduction: Temporary ileostomy is an emergency procedure performed in cases having septic peritonitis in presence of perforation or obstruction or gangrene of small intestine. These patients usually suffer from gross malnutrition following surgery.

Aim: To measure nutritional status of patients with emergency temporary ileostomy and to determine whether their postoperative nutrition can be favourably maintained by oral diet alone.

A Highly Selective Reaction-Based Two-Photon Probe for Copper(I) in Aqueous Media.

Out of the blue: A reaction-based two-photon probe XanCu is reported for the selective detection of Cu in reducing aqueous environments. Copper(I)-mediated oxidative benzylic ether (CO) bond cleavage offers "switch-on" detection of the metal ion.

A turn-on NIR fluorescence and colourimetric cyanine probe for monitoring the thiol content in serum and the glutathione reductase assisted glutathione redox process.

We report a novel reaction-based thiol selective turn-on near-infrared (NIR) fluorescence and colourimetric dinitrobenzenesulfonyl-cyanine (DNBSCy) probe. In the presence of thiols such as glutathione (GSH), new absorption bands (476 and 581 nm) were observed, with the colour of the solution (10 mM PBS, pH = 7.4) changing from light green to blue.

Reactive probes for ratiometric detection of Co2+ and Cu+ based on excited-state intramolecular proton transfer mechanism.

An excited-state intramolecular proton transfer (ESIPT) mechanism based two reactive probes HBTCo and HBTCu is reported for the selective detection of Co(2+) and Cu(+) respectively in a reducing aqueous environment. Co(2+) and Cu(+) mediated oxidative benzylic ether (C-O) bond cleavage offers ratiometric detection of these metal ions.

A differentially selective sensor with fluorescence turn-on response to Zn2+ and dual-mode ratiometric response to Al3+ in aqueous media.

A novel quinoline-coumarin (QC) fluoroionophore conjugated by means of a triazolyl-pyrrolidinyl linker exhibits differential dual selectivity for Zn(2+) and Al(3+) in mixed media. QC acts as a turn on fluorescence sensor for Zn(2+) while exhibiting overall ratiometric selectivity for Al(3+) in aqueous media. Moreover, QC exhibited preferential second mode of selectivity for Al(3+) as it ratiometrically displaces Zn(2+) from the [QC + Zn(2+)] complex.