An Amphiphilic Polymer-Supported Strategy Enables Chemical Transformations under Anhydrous Conditions for DNA-Encoded Library Synthesis.

The use of DNA-encoded libraries has emerged as a powerful hit generation technology. Combining the power of combinatorial chemistry to enumerate large compound collections with the efficiency of affinity selection in pools, the methodology makes it possible to interrogate vast chemical space against biological targets of pharmaceutical relevance. Thus, the chemical transformations employed for the synthesis of encoded libraries play a crucial role in the identification of diverse and drug-like starting points. Currently established transformations have mostly been limited to water-compatible reactions to accommodate the growing oligonucleotide tag. Herein, we describe the development of a practical catch-and-release methodology utilizing a cationic, amphiphilic PEG-based polymer to perform chemical transformations on immobilized DNA conjugates under anhydrous conditions. We demonstrate the usefulness of our APTAC (amphiphilic polymer-facilitated transformations under anhydrous conditions) approach by performing several challenging transformations on DNA-conjugated small molecules in pure organic solvents: the addition of a carbanion equivalent to a DNA-conjugated ketone in tetrahydrofuran, the synthesis of saturated heterocycles using the tin (Sn) amine protocol (SnAP) in dichloromethane, and the dual-catalytic (Ir/Ni) metallaphotoredox decarboxylative cross-coupling of carboxylic acids to DNA-conjugated aryl halides in DMSO. In addition, we demonstrate the feasibility of the latter in multititer-plate format.

Self-assembled peptide nanostructures targeting death receptor 5 and encapsulating paclitaxel as a multifunctional cancer therapy.

The development of tumor-targeted nanoscale carriers for the delivery of cancer therapeutics offers the ability to increase efficacy while limiting off-target toxicity. In this work we focused on targeting death receptor 5 (DR5), which is highly expressed by cancer cells, and upon binding, triggers programmed cell death. Hence, a nanostructure targeting DR5 would act as a dual targeting and therapeutic agent. We report here on a peptide amphiphile (PA) containing a dimeric, cyclic peptide that self-assembles into cylindrical supramolecular nanofibers and targets DR5. Coassembly of the DR5-targeting PA and a pegylated PA creates a supramolecular nanoscale construct with enhanced binding affinity to DR5 relative to a monomeric targeting PA, and was found to be cytotoxic in vitro. When combined with the chemotherapy paclitaxel, DR5-targeting carriers showed potent antitumor activity in vivo, demonstrating the multifunctional capabilities of peptide-based supramolecular nanostructures.

Efficient copper-catalyzed amination of DNA-conjugated aryl iodides under mild aqueous conditions.

Herein, we describe the development of copper-catalyzed cross-coupling of DNA-conjugated aryl iodides with aliphatic amines. This protocol leverages a novel ligand, 2-((2,6-dimethoxyphenyl)amino)-2-oxoacetic acid, to effect the transformation in aqueous DMSO, under mild conditions and in air, making it an ideal candidate for the synthesis of DNA-encoded libraries.

Reversible native chemical ligation: a facile access to dynamic covalent peptides.

The broad interest of using reversible covalent bonds in chemistry, in particular at its interfaces with biology and materials science, has been recently established through numerous examples in the literature. However, the challenging exchange of peptide fragments using a dynamic covalent peptide bond has not yet been achieved without enzymatic catalysis because of its high thermodynamic stability. Here we show that peptide fragments can be exchanged by a chemoselective and reversible native chemical ligation (NCL) which can take place at N-(methyl)-cysteine residues. This very mild reaction is efficient in aqueous solution, is buffered at physiological pH in the presence of dithiothreitol (DTT), and shows typical half-times of equilibration in the 10 h range.

Supramolecular self-assemblies as functional nanomaterials.

In this review, we survey the diversity of structures and functions which are encountered in advanced self-assembled nanomaterials. We highlight their flourishing implementations in three active domains of applications: biomedical sciences, information technologies, and environmental sciences. Our main objective is to provide the reader with a concise and straightforward entry to this broad field by selecting the most recent and important research articles, supported by some more comprehensive reviews to introduce each topic. Overall, this compilation illustrates how, based on the rules of supramolecular chemistry, the bottom-up approach to design functional objects at the nanoscale is currently producing highly sophisticated materials oriented towards a growing number of applications with high societal impact.

Precision templating with DNA of a virus-like particle with peptide nanostructures.

We report here the preparation of filamentous virus-like particles by the encapsulation of a linear or circular double-stranded DNA template with preassembled mushroom-shaped nanostructures having a positively charged domain. These nanostructures mimic the capsid proteins of natural filamentous viruses and are formed by self-assembly of coiled-coil peptides conjugated at opposite termini with cationic segments and poly(ethylene glycol) (PEG) chains. We found that a high molecular weight of PEG segments was critical for the formation of monodisperse and uniformly shaped filamentous complexes. It is proposed that electrostatic attachment of the nanostructures with sufficiently long PEG segments generates steric forces that increase the rigidity of the neutralized DNA template. This stiffening counterbalances the natural tendency of the DNA template to condense into toroids or buckle multiple times. The control achieved over both shape and dimensions of the particles offers a strategy to create one-dimensional supramolecular nanostructures of defined length containing nucleic acids.

Coassembled cytotoxic and pegylated peptide amphiphiles form filamentous nanostructures with potent antitumor activity in models of breast cancer.

Self-assembled peptide amphiphiles (PAs) consisting of hydrophobic, hydvrogen-bonding, and charged hydrophilic domains form cylindrical nanofibers in physiological conditions and allow for the presentation of a high density of bioactive epitopes on the nanofiber surface. We report here on the use of PAs to form multifunctional nanostructures with tumoricidal activity. The combination of a cationic, membrane-lytic PA coassembled with a serum-protective, pegylated PA was shown to self-assemble into nanofibers. Addition of the pegylated PA to the nanostructure substantially limited degradation of the cytolytic PA by the protease trypsin, with an 8-fold increase in the amount of intact PA observed after digestion. At the same time, addition of up to 50% pegylated PA to the nanofibers did not decrease the in vitro cytotoxicity of the cytolytic PA. Using a fluorescent tag covalently attached to PA nanofibers we were able to track the biodistribution in plasma and tissues of tumor-bearing mice over time after intraperitoneal administration of the nanoscale filaments. Using an orthotopic mouse xenograft model of breast cancer, systemic administration of the cytotoxic pegylated nanostructures significantly reduced tumor cell proliferation and overall tumor growth, demonstrating the potential of multifunctional PA nanostructures as versatile cancer therapeutics.

Glycodynamers: dynamic polymers bearing oligosaccharides residues--generation, structure, physicochemical, component exchange, and lectin binding properties.

Dynamic glycopolymers have been generated by polycondensation through acylhydrazone formation between components bearing lateral bioactive oligosaccharide chains. They have been characterized as bottlebrush type by cryo-TEM and SANS studies. They present remarkable fluorescence properties whose emission wavelengths depend on the constitution of the polymer and are tunable by constitutional modification through exchange/incorporation of components, thus also demonstrating their dynamic character. Constitution-dependent binding of these glycodynamers to a lectin, peanut agglutinin, has been demonstrated.

Glycodynamers: dynamic analogs of arabinofuranoside oligosaccharides.

Dynamic analogs of alpha-(1-->5)-D-oligoarabinofuranosides were prepared by oxime polycondensation. These equilibrium polymers were characterized by (1)H NMR studies, NMR DOSY, and MALDI mass spectrometry. Their reversibility under mild acidic conditions was demonstrated by component exchange reaction followed by (1)H NMR studies. Their size and composition can be tuned by component exchange emphasizing their constitutionally dynamic character. They represent dynamic versions of biopolymers, biodynamers.

1,3-disubstituted 4-aminopiperidines as useful tools in the optimization of the 2-aminobenzo[a]quinolizine dipeptidyl peptidase IV inhibitors.

In a search for novel DPP-IV inhibitors, 2-aminobenzo[a]quinolizines were identified as submicromolar HTS hits. Due to the difficult synthetic access to this compound class, 1,3-disubstituted 4-aminopiperidines were used as model compounds for optimization. The developed synthetic methodology and the SAR could be transferred to the 2-aminobenzo[a]quinolizine series, leading to highly active DPP-IV inhibitors.

Controlled release of volatile aldehydes and ketones by reversible hydrazone formation--classical" profragrances are getting dynamic.

Dynamic mixtures obtained by reversible covalent acylhydrazone formation of fragrance aldehydes and/or ketones and a hydrazide in water were found to be efficient delivery systems for the controlled release of highly volatile organic molecules.