Sequence-defined antibody-recruiting macromolecules.

Antibody-recruiting molecules represent a novel class of therapeutic agents that mediate the recruitment of endogenous antibodies to target cells, leading to their elimination by the immune system. Compared to single-ligand copies, macromolecular scaffolds presenting multiple copies of an antibody-binding ligand offer advantages in terms of increased complex avidity. In this study, we describe the synthesis of sequence-defined macromolecules designed for antibody recruitment, utilising dinitrophenol (DNP) as a model antibody-recruiting motif. The use of discrete macromolecules gives access to varying the spacing between DNP motifs while maintaining the same chain length. This characteristic enables the investigation of structure-dependent binding interactions with anti-DNP antibodies. Through solid-phase thiolactone chemistry, we synthesised a series of oligomers with precisely localised DNP motifs along the backbone and a terminal biotin motif for surface immobilisation. Utilising biolayer interferometry analysis, we observed that oligomers with adjacent DNP motifs exhibited enhanced avidity for anti-DNP antibodies. Molecular modelling provided insights into the structures and dynamics of the various macromolecules, shedding light on the accessibility of the ligands to the antibodies. Overall, our findings highlight that the use of sequence-defined macromolecules can contribute to our understanding of structure-activity relationships and provide insights for the design of novel antibody-recruiting therapeutic agents.

Ring-Opening Metathesis Polymerization for the Synthesis of Terpenoid-Based Pressure-Sensitive Adhesives.

Pressure-sensitive adhesives (PSAs) made from norbornene-functionalized terpenoid-based monomers are reported as a possible alternative to the conventional petrochemically based PSAs. For this, tetrahydrogeranyl, menthyl, and isobornyl norbornenate monomers, with a renewable carbon content up to 72%, are synthesized and copolymerized via ring-opening metathesis polymerization (ROMP) with cyclooctadiene and 5-norbornene-2-carboxylic acid. ROMP enables a much faster and controlled polymerization process in comparison to free radical polymerization techniques when targeting high molecular weights and therefore unlocks a potential to design a unique class of PSA materials. The moduli at bonding and debonding frequencies of the obtained PSAs are plotted in the Chang classification system and are used to predict their adhesive performance. Tack and peel measurements indicate that the terpenoid-based norbornenate formulations show similar adhesive properties in comparison to the previously investigated acrylic counterparts.

Sequence-Defined Mikto-Arm Star-Shaped Macromolecules.

The synthesis of sequence-defined, discrete star-shaped macromolecules is a major challenge due to the lack of straightforward and versatile approaches. Here, a robust strategy is proposed that allows not only the preparation of sequence-defined mikto-arm star-shaped macromolecules but also the synthesis of a series of unprecedented discrete, multifunctional complex architectures with molar masses above 11 kDa. The iterative approach reported makes use of readily available building blocks and results in asymmetrically branched macromolecules with high purity and yields, which is showcased with monodisperse mikto-arm three-, four-, and five-arm star-shaped structures that were all characterized via LC-MS, MALDI-ToF, and NMR. This effective strategy drastically improves upon synthetic abilities of polymer chemists by enabling simultaneously sequence definition, precision insertion of branching points, as well as the orthogonal end-group functionalization of complex polymeric architectures. The presented approach, which can be translated to different platforms such as peptides and peptoids, is therefore particularly interesting in biomedical applications for which multiple different functional moieties on a single discrete macromolecule are needed.

Applications of Discrete Synthetic Macromolecules in Life and Materials Science: Recent and Future Trends.

In the last decade, the field of sequence-defined polymers and related ultraprecise, monodisperse synthetic macromolecules has grown exponentially. In the early stage, mainly articles or reviews dedicated to the development of synthetic routes toward their preparation have been published. Nowadays, those synthetic methodologies, combined with the elucidation of the structure-property relationships, allow envisioning many promising applications. Consequently, in the past 3 years, application-oriented papers based on discrete synthetic macromolecules emerged. Hence, material science applications such as macromolecular data storage and encryption, self-assembly of discrete structures and foldamers have been the object of many fascinating studies. Moreover, in the area of life sciences, such structures have also been the focus of numerous research studies. Here, it is aimed to highlight these recent applications and to give the reader a critical overview of the future trends in this area of research.

Sequence-Encoded Macromolecules with Increased Data Storage Capacity through a Thiol-Epoxy Reaction.

Sequence-encoded oligo(thioether urethane)s with two different coding monomers per backbone unit were prepared via a solid phase, two-step iterative protocol based on thiolactone chemistry. The first step of the synthetic cycle consists of the thiolactone ring opening with a primary amine, whereby the in situ released thiol is immediately reacted with an epoxide. In the second step, the thiolactone group is reinstalled to initiate the next cycle. This strategy allows to introduce two different coding monomers per synthetic cycle, rendering the resulting macromolecules especially attractive in the area of (macro)molecular data storage because of their increased data storage capacity. Subsequently, the efficiency of the herein reported synthesis route and the applicability of the dual-encoded sequence-defined macromolecules as a potential data storage platform have been demonstrated by unraveling the exact monomer order using tandem mass spectrometry techniques.

Effect of Arm Number and Length of Star-Shaped Glycopolymers on Binding to Dendritic and Langerhans Cell Lectins.

Many cell types in Nature are covered by glycans with a sugar shell on their surface. Synthetic glycopolymer-based materials can mimic these glycans in terms of their variety of biological processes, such as cell growth regulation, adhesion, inflammation by bacteria and viruses, and immune responses. However, the complexity of glycans is still very challenging to be mimicked completely to obtain specific and selective binding ability. Therefore, in this study we aimed to understand how the complexity in the sense of the effect of number of arms and lengths in star-shaped glycopolymers affect the binding activity with different lectins. The Cu-mediated reversible deactivation radical polymerization (Cu-RDRP) technique was employed for the synthesis of mannose containing star-shaped glycopolymers with varying arm number and length. Two sets of star-shaped glycopolymers with on average 1, 3, 7, 8, and 15 arms were successfully synthesized and characterized via 1H NMR, GPC, and DLS. The first set of glycopolymers (Set S1) encompasses 5 star-shaped glycopolymers with a different amount of arms per macromolecule but with equal arm length, whereas in the second set of 5 glycopolymers (Set S2), the amount of sugars per macromolecule was kept constant to obtain glycopolymers with similar glycovalency but in different configuration. Both glycopolymer sets were subsequently evaluated for their lectin-binding affinity toward a series of both newly and previously studied C-type mannose specific lectins present on dendritic and Langerhans cells. Briefly, while Set S1 glycopolymers with the same arm length and different molecular weight showed considerably different biological activities, Set S2 glycopolymers with different arm lengths and the same molecular weight displayed very similar binding abilities, which can indicate that multivalency can be more important than structure complexity to improve the binding behavior of glycopolymers.

Transformation of Thioester-Initiated Star Polymers into Linear Arms via Native Chemical Ligation.

The synthesis of a new class of Cu-mediated polymerization initiators with thioester functionality is demonstrated and their polymerization kinetics via single-electron transfer living radical polymerization is reported. From periodic sampling, it is found that thioester- or ester-based initiators can be employed interchangeably, resulting in very similar polymerization rates. Furthermore, a multifunctional thioester initiator is employed for the preparation of a well-defined four-arm star-shaped polymer. It is further shown that the full dissociation of the star polymer into linear arms via native chemical ligation can easily be followed via size exclusion chromatography, as a result of the change in hydrodynamic volume. Finally, the obtained linear polymers are characterized via matrix-assisted laser desorption/ionization-time of flight mass spectrometry and found to be in good agreement with the expected molecular weight distribution that confirms the successful transformation.