Juan R. Granja

Self Assembling Organic Nanotubes

Hollow tubular structures of molecular dimensions perform diverse biological functions in nature. Examples include scaffolding and packaging roles played by cytoskeletal microtubules and viral coat proteins, respectively, as well as the chemical transport and screening activities of membrane channels. In the preparation of such tubular assemblies, biological systems make extensive use of self-assembling and self-organizing strategies. Owing to numerous potential applications in areas such as chemistry, biology, and materials science considerable effort has recently been devoted to preparation of artificial nanotubular structures. This article reviews design principles and the preparation of synthetic organic nanotubes, with special emphasis on noncovalent processes such as self-assembly and self-organization.

Organische Nanoröhren durch Selbstorganisation

Rohrenformige molekulare Strukturen nehmen in der Natur verschiedenste biologische Funktionen wahr, erwahnt seien ihre Rolle beim Aufbau des Gerusts der Mikrotubuli des Cytoskeletts, die Verpackungsfunktion viraler Hullenproteine und ihre Funktion beim Transport von Molekulen sowie beim Screening von Transmembrankanalen. Beim Aufbau solcher tubularer Strukturen nutzen biologische Systeme ausgiebig die Selbstassoziation und Selbstorganisation molekularer Einheiten. Wegen der zahlreichen Anwendungsmoglichkeiten in der Chemie, der Biologie und den Materialwissenschaften wurden in der letzten Zeit betrachtliche Anstrengungen zur Herstellung kunstlicher Nanorohren unternommen. Dieser Aufsatz gibt einen Uberblick uber die Prinzipien des Designs und der Herstellung synthetischer organischer Nanorohren mit dem Schwerpunkt auf Aggregation uber nichtkovalente Wechselwirkungen wie der Selbstorganisation und Selbstassoziation.

Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides

ABSTRACT Cyclic peptides with an even number of alternating d,l-α-amino acid residues are known to self-assemble into organic nanotubes. Such peptides previously have been shown to be stable upon protease treatment, membrane active, and bactericidal and to exert antimicrobial activity against Staphylococcus aureus and other gram-positive bacteria. The present report describes the in vitro and in vivo pharmacology of selected members of this cyclic peptide family. The intravenous (i.v.) efficacy of six compounds with MICs of less than 12 μg/ml was tested in peritonitis and neutropenic-mouse thigh infection models. Four of the six peptides were efficacious in vivo, with 50% effective doses in the peritonitis model ranging between 4.0 and 6.7 mg/kg against methicillin-sensitive S. aureus (MSSA). In the thigh infection model, the four peptides reduced the bacterial load 2.1 to 3.0 log units following administration of an 8-mg/kg i.v. dose. Activity against methicillin-resistant S. aureus was similar to MSSA. The murine pharmacokinetic profile of each compound was determined following i.v. bolus injection. Interestingly, those compounds with poor efficacy in vivo displayed a significantly lower maximum concentration of the drug in serum and a higher volume of distribution at steady state than compounds with good therapeutic properties. S. aureus was unable to easily develop spontaneous resistance upon prolonged exposure to the peptides at sublethal concentrations, in agreement with the proposed interaction with multiple components of the bacterial membrane canopy. Although additional structure-activity relationship studies are required to improve the therapeutic window of this class of antimicrobial peptides, our results suggest that these amphipathic cyclic d,l-α-peptides have potential for systemic administration and treatment of otherwise antibiotic-resistant infections.

α,γ-Peptide nanotube templating of one-dimensional parallel fullerene arrangements

The formation and full characterization of single self-assembling alpha,gamma-peptide nanotubes (alpha,gamma-SPNs) is described. The introduction of C(60) into cyclic peptides allows the preparation of supramolecular 1D fullerene arrangements induced by peptide nanotube formation under appropriate conditions.

Electron transfer in Me-blocked heterodimeric α,γ-peptide nanotubular donor–acceptor hybrids

Bio-inspired cyclopeptidic heterodimers built on β-sheet-like hydrogen-bonding networks and bearing photoactive and electroactive chromophores on the outer surface have been prepared. Different cross-strand pairwise relationships between the side chains of the cyclic α,γ-peptides afford the heterodimers as three nonequivalent dimeric species. Steady-state and time-resolved spectroscopies clearly show an electron transfer process from π-extended tetrathiafulvalene, covalently attached to one of the cyclopeptides, to photoexcited [60]fullerene, located on the complementary cyclopeptide. The charge-separated state was stabilized for up to 1 μs before recombining and repopulating the ground state. Our current example shows that cyclopeptidic templates can be successfully used to form light-harvesting/light-converting hybrid ensembles with a distinctive organization of donor and acceptor units able to act as efficient artificial photosystems.

Folding Control in Cyclic Peptides through N‐Methylation Pattern Selection: Formation of Antiparallel β‐Sheet Dimers, Double Reverse Turns and Supramolecular Helices by 3α,γ Cyclic Peptides

Peptide foldamers constitute a growing class of nanomaterials with potential applications in a wide variety of chemical, medical and technological fields. Here we describe the preparation and structural characteristics of a new class of cyclic peptide foldamers (3alpha,gamma-CPs) that, depending on their backbone N-methylation patterns and the medium, can either remain as flat rings that dimerize through arrays of hydrogen bonds of antiparallel beta-sheet type, or can fold into twisted double reverse turns that, in the case of double gamma-turns, associate in nonpolar solvents to form helical supramolecular structures. A 3alpha,gamma-CP consists of a number of multiples of a repeat unit made up of four amino acid residues of alternating chirality: three corresponding to alpha-amino acids and one to a gamma-amino acid (a cis-3-aminocycloalkanecarboxylic acid).

Transmembrane ion transport by self-assembling α,γ-peptide nanotubes

In this study, we describe the self-assembling properties of cyclic peptides containing γ-amino acids in lipid bilayers to form transmembrane nanotubes. The resulting ion channel models are selective for alkaline ions. Although the transport rates conform to the lyotropic series, these partially hydrophobic channels show an unexpectedly higher rate for sodium ions.

Theoretical Characterization of the Dynamical Behavior and Transport Properties of α,γ-Peptide Nanotubes in Solution

We present here a molecular dynamics study on a promising class of peptide nanotubes with a partially hydrophobic inner cavity and an easy chemical functionalization of the lumen of the cylindrical structure. The structural and dynamical behavior of the nanotube in water, methanol, and chloroform has been analyzed using state of the art theoretical methods. The nanotube structure is always well preserved, but solvent-dependent dynamic alterations are evident. Such dynamic effects are surprisingly more severe in the most viscous solvent (water), as a consequence of the competition in polar solvents between intra- and intermolecular hydrogen bonds. Stiffness analysis from the collected trajectories helped us to characterize the equilibrium deformability of the nanotube, while steered dynamics simulations were used to determine the magnitude of free energy associated with nanotube growth. Analysis of the carrier and permeation properties of the compounds reveals surprising properties: (i) permeability for the most polar solvent (water), (ii) carrier properties for the most apolar solvent (chloroform), and (iii) neither good permeation nor carrier properties for the intermediate solvent in polarity (methanol). Results reported here constitute the most extensive characterization of these nanotubes presented to date and open many intriguing questions on their stability, dynamics, and transport/carrier properties.

In Situ Functionalized Polymers for siRNA Delivery.

A new method is reported herein for screening the biological activity of functional polymers across a consistent degree of polymerization and in situ, that is, under aqueous conditions and without purification/isolation of candidate polymers. In brief, the chemical functionality of a poly(acryloyl hydrazide) scaffold was activated under aqueous conditions using readily available aldehydes to obtain amphiphilic polymers. The transport activity of the resulting polymers can be evaluated in situ using model membranes and living cells without the need for tedious isolation and purification steps. This technology allowed the rapid identification of a supramolecular polymeric vector with excellent efficiency and reproducibility for the delivery of siRNA into human cells (HeLa-EGFP). The reported method constitutes a blueprint for the high-throughput screening and future discovery of new polymeric functional materials with important biological applications.

Interaction and Dimerization Energies in Methyl-Blocked α,γ-Peptide Nanotube Segments

The building blocks of a promising class of peptide nanotubes composed of alternating D-alpha-amino acids and (1R,3S)-3-aminocyclohexane (or cyclopentane) carboxylic acid (D-gamma-Ach or D-gamma-Acp) were explored by computational methods. Specifically, density functional theory (DFT) calculations on monomers and dimers of gamma-Ach-based and gamma-Acp-based alpha,gamma-cyclo-hexapeptides and cyclo-octapeptides were carried out to investigate the experimentally observed preference for alpha-alpha over gamma-gamma dimerization, associated with the two types of stacking patterns present in these peptide nanotubes, as well as the preference for heterodimerization versus homodimerization. Full geometry optimizations were performed at the B3LYP/6-31G(d) level, and single point calculations were subsequently carried out with the B3LYP and M05-2X functionals and the 6-31+G(d,p) basis set. The calculations predict that the interaction energies in the alpha-alpha species are quite similar to those in the gamma-gamma dimers. However, a comparison of dimerization energies (i.e., interaction energies plus deformation energies of monomers) shows that alpha-alpha dimerization is energetically favored over gamma-gamma dimerization. The calculations strongly suggest that the preference for alpha-alpha binding is governed by differences between the deformation energies in the alpha and gamma monomers, rather than by differences between the relative strengths of the alpha-alpha and gamma-gamma hydrogen-bonding patterns. Calculations based on local properties of the electron density support the previous suggestion that the H-N bonds of the alpha-amino acids are more polarized than those of the gamma-amino acids.