Research Field 3

Sen, N. et. al. RSC Chemical Biology, 2024, 5, 1248-1258,  https://pubs.rsc.org/en/Content/ArticleLanding/2024/CB/D4CB00217B

Solubility and aggregation of proteins are crucial factors for their functional and further biological roles. Aggregation of proteins in vivo, such as the amyloid beta (Aβ_1–40) peptide into fibrils, is significantly modulated by membrane lipids, abundantly present in cells. We developed a model membrane system, composed of lipid hybrid-vesicles bearing embedded hydrophilic polymers to in vitro study the aggregation of the Aβ_1–40 peptide. Focus is to understand and inhibit the primordial, nucleation stages of their fibrillation by added hybrid-vesicles, composed of a natural lipid and amphiphilic polymers. These designed hybrid-vesicles are based on 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), displaying embedded hydrophilic (EO)_mP_nA_EG polymers (m = 2 or 3; P_n = 10 to 52 with M_n = 2800–9950 gmol⁻¹) in amounts ranging from 5–20 mol%, anchored to the POPC vesicles via hydrophobic hexadecyl-, glyceryl- and cholesteryl-moieties, affixed to the polymers as end-groups. All investigated hybrid-vesicles significantly delay fibrillation of the Aβ_1–40 peptide as determined by thioflavin T (ThT) assays. We observed that the hybrid-vesicles interacted with early aggregating species of Aβ_1–40 peptide, irrespective of their composition or size. A substantial perturbation of both primary (k₊k_n) and secondary (k₊k₂) nucleation rates of Aβ_1–40 by the POPC–polymer vesicles compared to POPC vesicles was observed, particularly for the cholesteryl-anchored polymers, interfering with the fragmentation and elongation steps of Aβ_1–40.. Reproduced with permission from the Royal Society of Chemistry.

Paschold, A. et. al. Bioconjugate Chemistry, 2024, 35, 7, 981–995, https://doi.org/10.1021/acs.bioconjchem.4c00188

Peptide fibrillization is crucial in biological processes such as amyloid-related diseases and hormone storage, involving complex transitions between folded, unfolded, and aggregated states. We here employ light to induce reversible transitions between aggregated and nonaggregated states of a peptide, linked to the parathyroid hormone (PTH). The artificial light-switch 3-{[(4-aminomethyl)phenyl]diazenyl}benzoic acid (AMPB) is embedded into a segment of PTH, the peptide PTH25–37, to control aggregation, revealing position-dependent effects. Through in silico design, synthesis, and experimental validation of 11 novel PTH25–37-derived peptides, we predict and confirm the amyloid-forming capabilities of the AMPB-containing peptides. Quantum-chemical studies shed light on the photoswitching mechanism. Solid-state NMR studies suggest that β-strands are aligned parallel in fibrils of PTH25–37, while in one of the AMPB-containing peptides, β-strands are antiparallel. Simulations further highlight the significance of π–π interactions in the latter. Copyright © 2024 The Authors. Published by American Chemical Society. This publication is licensed under  CC-BY 4.0

Rohmer, M. et.al., Chemistry – A European Journal, 2023, e202302585, e202302585, https://doi.org/10.1002/chem.202302585

The single-crystal ring-opening polymerization of α-aminoisobutyric acid- (Aib) and 1-aminocyclohexanecarboxylic acid- (ACHC) N-carboxyanhydrides (NCAs) is reported. Topochemical, living ring-opening polymerization (ROP) of these achiral amino-acid NCAs produces polymers of highest purity with increased chain length and high end-group fidelity as compared to conventional solution polymerization. © 2023 The Authors. Chemistry – A European Journal published by Wiley-VCH GmbH

Rohmer, M. et al., Macromolecular Biosciences, 2023, 2200344,

https://doi.org/10.1002/mabi.202200344

The secondary structure of poly(amino acids) is an excellent tool for controlling and understanding the functionality and properties of proteins. In this perspective article the secondary structures of the homopolymers of oligo- and poly-glutamic acid (Glu), aspartic acid (Asp), and α-aminoisobutyric acid (Aib) are discussed. Information on external and internal factors, such as the nature of side groups, interactions with solvents and interactions between chains is reviewed. As polymer- and amino acid folding is an important step for the utilization and design of future biomaterials useful for cell-adhesion and embedding, such hybrid materials open a future perspective for biomedicines. © 2023 The Authors. Macromolecular Bioscience published by Wiley‐VCH GmbH.

Sen, N. et al., Macromolecular Bioscience, 2023, 2200522, DOI:10.1002/mabi.202200522

The transformation of functional proteins into amyloidic plaques is responsible for the impairment of neurological functions in patients fallen victim to debilitating neurological conditions like Alzheimer’s, Parkinson’s, and Huntington’s diseases. We investigate the influence of lipid hybrid-vesicles on alterations of the nucleation process and thus early phases of Aβ_1-40 fibrillation. Hybrid-vesicles (±100 nm) are prepared by incorporating variable amounts of cholesterol-/glycerol-conjugated poly(di(ethylene glycol)_macrylates)_n polymers into 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membranes. Such polymers, when embedded in hybrid-vesicles (up to 20%) significantly prolonged the fibrillation lag phase (t_lag) compared to a small acceleration in the presence of DOPC vesicles, irrespective of the amount of polymers inside the hybrid-vesicles. © 2023 The Authors. Macromolecular Bioscience published by Wiley‐VCH GmbH.

Rupali, J. B. et al., Polymer Chemistry, 2023, 392-411,

http://dx.doi.org/10.1039/D2PY01217K

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with no current cure and limited treatment solutions, wherefore discovering of novel therapies remains a global challenge in biopharmaceutical industries. This review article aims to summarize articles documenting synthetic polymer-based inhibitors of Aβ aggregations and highlight their potential as promising AD therapeutic agents. Published with a permission of the Royal Society of Chemistry 2023.

Paschold, A., et al. Biomedicines, 2022, DOI:https://doi.org/10.3390/biomedicines10071512

We here report a novel strategy to control the bioavailability of the fibrillizing parathyroid hormone (PTH)-derived peptides, where the concentration of the bioactive form is controlled by an reversible, photoswitchable peptide. We embed the azobenzene derivate 3-{[(4-aminomethyl)phenyl]diazenyl}benzoic acid (3,4′-AMPB) into the PTH-derived peptide PTH_25–37 to generate the artificial peptide AzoPTH_25–37 via solid-phase synthesis. The trans-form of AzoPTH_25–37 fibrillizes similar to PTH_25–37, while the cis-form of AzoPTH_25–37 generates only amorphous aggregates. The approach reported here is designed to control the concentration of PTH-peptides, where the bioactive form can be catalytically controlled by an added photoswitchable peptide.

Rohmer, M.. et. al. Polymer Chemistry, 2021, 12, 6252-6262, DOI: 10.1039/D1PY01021B

2-Aminoisobutyric acid (Aib) is a prominent achiral amino acid known for its helical building properties, generating left- and right-handed helices without any preference. We here report on several short chain poly(Aib)s synthesized by ring opening polymerization (ROP) of Aib-N-carboxy-anhydrides (Aib-NCA) with structurally different chiral amines acting as both, initiator and chiral induction agent. By adding a chiral center at the C-terminus of the polymer chain we can control the direction of the screw sense, since the polymers are adopting the chirality of the initiator following the sergeant-and-soldier principle. Variation of the solvent from hexafluoroisoropanol (HFIP) to water resulted in a significant change of CD signals, featuring a surprising aggregation of the poly(amino acids) into globular aggregates in water in the range of 50 to 200 nm, which accounts for changes in chiral induction. Published with a permission of the Polymer Chemistry 2021.

Sen, N. et. al., Macromolecular Rapid Communication, 2021, 2100120, https://doi.org/10.1002/marc.202100120

We here report on the influence of conjugates fabricated from lipid anchors (cholesterol, diacylglycerol) and hydrophilic polymers on Aβ_1-40 fibrillation, aiming to understand the impact of polymers cloud point temperature (T_cp) and its hydrophobic tails on the amyloid fibrillation. Novel lipid-polymer conjugates, consisting of poly(oligo(ethylene glycol)_macrylates) and hydrophobic groups (diacylglyceryl-, cholesteryl-, octyl-, decyl-, hexadecyl-) as anchors are synthesized  via RAFT polymerization, allowing to tune the hydrophilic-hydrophobic profile of the conjugates. Hydrophobic lipid-anchors are significantly delaying fibrillation (both lag, t_lag and half times, t_1/2), observing similar fibrillar structures via TEM when compared to native Aβ_1-40. © 2021 The Authors. Macromolecular Rapid Communications published by Wiley‐VCH GmbH

Kumar, S., et al. Soft Matter, 2020, 16,6964-6968, DOI: 10.1039/D0SM01169J

We here describe the synthesis of a novel  peptide/polymer-conjugate, embedding the amyloid-β (Aβ) protein core sequence Leu-Val-Phe-Phe (LVFF, Aβ_17-20) via RAFT polymerization. Based on a novel chain transfer-agent, the “grafting-from” approach effectively generates the well-defined peptide-polymer conjugates with appreciably high monomer conversion rate, resulting in mechanically stiffer peptide-functional cross-linked polymeric hydrogels. Reproduced by permission of The Royal Society of Chemistry 2020.